AU2019226219A1 - Genetic factors associated with inhibitor development in hemophilia a - Google Patents

Abstract

The present invention provides methods for predicting the risk of an individual developing antibodies to factor Vill by identifying a single nucleotide polymorphism of an immune response or immune modifier gene. The invention further provides oligonucleotides, diagnostic kits, microarrays, and isolated nucleic acids comprising single nucleotide polymorphisms of immune response or immune modifier genes.

Description

GENETIC FACTORS ASSOCIATED WITH INHIBITOR DEVELOPMENT

IN HEMOPHILIA A

CROSS-REFERENCES TO RELATED APPLICATIONS [0001] The present application claims the benefit of U.S. Provisional Application No.

61/326,602, filed April 21, 2010, which is expressly incorporated herein by reference in its entirety for all purposes.

BACKGROUND OF THE INVENTION [0002] Blood coagulation is a complex and dynamic biological process that depends on a series of interdependent biochemical reactions. Coagulation factor VIII (FVIII) is a key component of the blood coagulation cascade.

[0003] When a bleed occurs, FVIII is directed to the bleeding site and forms a Xase complex with activated factor IX (FIXa) and factor X (FX). The Xase complex activates FX, which in turn activates prothrombin to thrombin, which activates other components in the coagulation cascade to generate a stable clot (reviewed in Saenko et al., Trends Cardiovasc. Med., 9:185-192 5 (1999); Lenting et al., Blood, 92:3983-3996 (1998)).

[0004] In hemophilia A, a congenital X-linked bleeding disorder characterized by a deficiency in FVIII, the lack of functional FVIII hampers this positive feedback loop, resulting in incomplete coagulation, which manifests as bleeding episodes of increased duration rather than increased intensity (Zhang et al., Clinic. Rev. Allerg. Immunol., 37:114-124 (2009)).

[0005] The severity of hemophilia A varies based on the nature of any mutation to FVIII and the extent of function of any endogenous FVIII that is formed. About two thirds of patients have severe hemophilia, characterized as less than 1% functional FVIII. Patients with moderate hemophilia have about 1-5% functional FVIII, and patients with mild hemophilia have about

5-50% of normal FVIII function (Zhang et al., Clinic. Rev. Allerg. Immunol., 37:114-124 (2009)). Current treatment for hemophilia typically consists of factor VIII replacement therapy, in which the patient receives recombinant or plasma-derived factor VIII to prevent or treat bleeding episodes. However, in approximately 25-30% of patients with severe hemophilia A and in approximately 5% of patients with mild to moderate hemophilia A, inhibitory alloantibodies are produced against FVIII, abrogating the effectiveness of this treatment (Oldenburg and

Pavlova, Haemophilia, 12 (suppl. 6):15-22 (2006)).

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 [0006] Inhibitor development is considered to be the most significant complication in the treatment of hemophilia. Patients with inhibitors have a higher mortality rate because their bleeding episodes become more difficult and costly to treat, and preventative treatment is generally not possible in these patients. In patients with high-titer inhibitors, there is an increased risk of developing recurrent bleeding in particular joints, which may ultimately result in decreased quality of life, disability, or death from excessive blood loss (Zhang et al., Clinic. Rev. Allerg. Immunol., 37:114-124 (2009); Gouw and van den Berg, Semin. Thromb. Hemost., 35:723-734 (2009)). Although in some cases immune tolerance induction can eradicate FVIII inhibitors in patients with hemophilia A, relapse is possible and not all patients reach immune tolerance (Wight et al., Haemophilia, 9:436-463 (2003)).

[0007] Accordingly, there is a need in the art for the identification of genetic markers that are associated with increased likelihood of developing inhibitory antibodies to FVIII and for corresponding methods of identifying the presence of these genetic markers in hemophiliac patients. Prior or early identification of such genetic markers could lead to dose and/or timing adjustments and to the use of alternative therapies to avoid the development of antibodies to FVIII.

BRIEF SUMMARY OF THE INVENTION [0008] In one aspect, the present invention provides a method for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, 0 the method comprising the steps of: (a) detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4, in a biological sample from the individual; and (b) predicting the risk of the individual of developing antibodies to FVIII. In a preferred embodiment, the at least one SNP is selected from those listed in Table 3. In another 25 preferred embodiment, the at least one SNP is selected from the group consisting of rs 12368829, rsl 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, andrsl7725712.

[0009] In a second aspect, the present invention provides a method for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with severe

Hemophilia, the method comprising the steps of: (a) detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 and a SNP listed in Table 4, in a biological sample from the individual; and (b) predicting the risk of the individual of developing antibodies to FVIII. In a preferred embodiment, the at least one SNP is selected from those listed in Table 4. In another preferred embodiment, the at least one SNP is selected from the group consisting of rsl2368829, rs4147385, rsl 1744216, rsl863993, rsl7535213, rsl0072056, rsl0054825, rsl2546235, rs4242389, rs2071336, rs414634, rs 17725712, rsl 1773821, rs8005905, and rs9482888.

[0010] In a third aspect, the present invention provides a method for assigning treatment comprising administration of Factor VIII (FVIII) to an individual diagnosed with Hemophilia, the method comprising the steps of: (a) detecting the presence of at least one single nucleotide 0 polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4, in a biological sample from the individual; and (b) predicting the risk of the individual of developing antibodies to FVIII, and (c) assigning therapy comprising administration of Factor VIII to the individual. In a preferred embodiment, the at least one SNP is selected from those listed in Table 3. In another preferred embodiment, the at least one SNP is selected from the group consisting of rs 12368829, rsl 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712.

[0011] In a fourth aspect, the present invention provides a method for assigning treatment comprising administration of Factor VIII (FVIII) to an individual diagnosed with severe 0 Hemophilia, the method comprising the steps of: (a) detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4, in a biological sample from the individual; and (b) predicting the risk of the individual of developing antibodies to FVIII, and (c) assigning therapy comprising administration of Factor VIII to the individual. In a preferred embodiment, the at least one SNP 25 is selected from those listed in Table 4. In another preferred embodiment, the at least one SNP is selected from the group consisting of rsl2368829, rs4147385, rsl 1744216, rsl863993, rs 17535213, rs 10072056, rs 10054825, rs 12546235, rs4242389, rs2071336, rs414634, rsl7725712, rsl 1773821, rs8005905, and rs9482888.

[0012] In a fifth aspect, the present invention provides a method for assigning treatment comprising administration of Factor VIII bypass therapy to an individual diagnosed with

Hemophilia, the method comprising the steps of: (a) detecting the presence of at least one single

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4, in a biological sample from the individual; and (b) predicting the risk of the individual of developing antibodies to FVIII, and (c) assigning therapy comprising administration of Factor VIII bypass therapy to the individual. In a preferred embodiment, the at least one SNP is selected from those listed in Table 3. In another preferred embodiment, the at least one SNP is selected from the group consisting of rsl2368829, rsll744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712.

[0013] In a sixth aspect, the present invention provides a method for assigning treatment comprising administration of Factor VIII bypass therapy to an individual diagnosed with severe Hemophilia, the method comprising the steps of: (a) detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4, in a biological sample from the individual; and (b) predicting the risk of the individual of developing antibodies to FVIII, and (c) assigning therapy comprising administration of Factor VIII bypass therapy to the individual. In a preferred embodiment, the at least one SNP is selected from those listed in Table 4. In another preferred embodiment, the at least one SNP is selected from the group consisting of rsl2368829, rs4147385, rsi 1744216, rsl863993, rsl7535213, rsl0072056, rsl0054825, rsl2546235, rs4242389, rs2071336, rs414634, rs 17725712, rsi 1773821, rs8005905, and rs9482888.

[0014] In a seventh aspect, the present invention provides a diagnostic kit for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the kit comprising at least one oligonucleotide capable of being used to detect at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4. In 25 a preferred embodiment, the at least one SNP is selected from those listed in Table 3. In another preferred embodiment, the at least one SNP is selected from the group consisting of rs 12368829, rsi 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712.

[0015] In an eighth aspect, the present invention provides a diagnostic kit for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with severe Hemophilia, the kit comprising at least one oligonucleotide capable of being used to detect at

WO 2011/131774

PCT/EP2011/056471 least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4. In a preferred embodiment, the at least one SNP is ^H selected from those listed in Table 4. In another preferred embodiment, the at least one SNP is selected from the group consisting of rsl2368829, rs4147385, rsi 1744216, rsl863993, rs 17535213, rs 10072056, rs 10054825, rs 12546235, rs4242389, rs2071336, rs414634, rsl7725712, rsi 1773821, rs8005905, and rs9482888.

[0016] In a ninth aspect, the present invention provides a microarray for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the microarray comprising a support having a plurality of discrete regions, each discrete region having a nucleic acid fragment spotted thereon, wherein at least one nucleic acid fragment spotted on the support comprises a sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4. In a preferred embodiment, the at least one SNP is selected from those listed in Table 3. In another preferred embodiment, the at least one SNP is selected from the group consisting of rs 12368829, rsi 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712.

[0017] In a tenth aspect, the present invention provides a microarray for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with severe

Hemophilia, the microarray comprising a support having a plurality of discrete regions, each discrete region having a nucleic acid fragment spotted thereon, wherein at least one nucleic acid fragment spotted on the support comprises a sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4. In a preferred embodiment, the at least 25 one SNP is selected from those listed in Table 4. In another preferred embodiment, the at least one SNP is selected from the group consisting of rsl2368829, rs4147385, rsi 1744216, rsl863993, rsl7535213, rsl0072056, rsl0054825, rsl2546235, rs4242389, rs2071336, rs414634, rs 17725712, rs 11773821, rs8005905, and rs9482888.

WO 2011/131774

PCT/EP2011/056471

BRIEF DESCRIPTION OF THE DRAWINGS [0018] Table 1. SNPs associated with inhibitor status in the Hemophilia Inhibitor Genetics ^H Study (HIGS) Combined Cohort, as determined in the study described in Example 1.

[0019] Table 2. SNPs associated with inhibitor status in a subgroup of individuals with severe hemophilia, as determined in the study described in Example 1.

[0020] Table 3. SNPs associated with inhibitor status in the Hemophilia Inhibitor Genetics Study (HIGS) Combined Cohort, as determined in the study described in Example 2.

[0021] Table 4. SNPs associated with inhibitor status in a subgroup of individuals with severe hemophilia, as determined in the study described in Example 2.

DETAILED DESCRIPTION OF THE INVENTION

I. Introduction [0022] The development of inhibitory alloantibodies against factor VIII is intricately connected with an individual's immune response to FVIII. For this reason, it has been proposed that risk factors associated with inhibitor development may include genotypes or polymorphisms associated with immune and inflammatory response. The immune response to FVIII is believed to develop as an immune response to an external antigen: the antigen is recognized and processed by antigen-presenting cells (APCs) into smaller fragments, then presented on the surface of the APCs in association with major histocompatibility complex (MHC) class II molecules, where it can be recognized by CD4+ T cells specific for FVIII, which in turn, in the zO presence of costimulatory signals, direct B cells to generate antibodies to FVIII (reviewed in Reding, Haemophilia, 12 (Suppl. 6):30-36 (2006)).

[0023] Several studies have found a weak association between MLC/human leukocyte antigen (HLA) class I alleles A3, B7, and C7, and MLC/HLA class II alleles DQA0102, DQB0602, DR 15 and higher risk of inhibitor development, while HLA class I allele C2 and HLA class II 25 alleles DQA0103, DQB0603, and DR13 were weakly associated with a protective effect against inhibitor development (Oldenburg et al., Thromb Haemost, 77:238-242 (1997); Hay et al., Thromb Haemost, 77:234-237 (1997)). However, other studies, including the more recent Malmo International Brother Study (MIBS), have not found any associations between HLA genotype and inhibitor development (Lippert et al., Thromb Haemost, 64:564-568 (1990);

Astermark et al., Blood, 108:3739-3745 (2006)). Other studies have found associations between

WO 2011/131774

PCT/EP2011/056471 inhibitor development and a single nucleotide polymorphism (SNP) in the promoter region of TNFA, encoding the immunomodulatory and pro-inflammatory cytokine tumor necrosis factor a ^H (Astermark et al., Blood, 108:3739-3745 (2006)); a 134 bp long variant of a CA repeat microsatellite in the promoter region of IL10, encoding the anti-inflammatory cytokine interleukin-10 (Astermark et al., Blood, 107:3167-3172 (2006)); and a SNP in the promoter region of CTLA4, encoding cytotoxic T-lymphocyte associated protein-4, a receptor mainly displayed on activated T-cells (Astermark et al., J. Thromb. Haemost., 5:263-265 (2007)). However, no association was found between inhibitor development and polymorphisms in ILlbeta and IL4, which encode cytokines and which have both been associated with risk of developing other autoimmune disorders (Astermark et al., Blood, 107:3167-3172 (2006)). It is clear that other genetic markers influencing the immune response to FVIII remain to be identified. Recently, Pavlova et al. (Pavlova A et al., Haemophilia 2010 May;16(102):107-12) identified a significantly higher frequency of DRB1*16 [odds ratio (OR) 10.2, 95%CI: 5.3219.57, P < 0.0001] and DQBl*0502 (OR 2.2, 95%CI: 1.12-4.54, P < 0.05) HLA class II aides was observed in patients with acquired hemophilia A (AH). In contrast, the frequency of DRB1*15 and DQB 1*0602 alleles was found to be decreased in patients with AH corresponding to an OR of 0.4 for both HLA loci.

[0024] The present invention relates to the discovery that SNPs in multiple other immune response, immune modulator, and inflammatory response genes are associated with inhibitor development in hemophiliac patients. In the present invention, a combined cohort of three study populations, the Hemophilia Inhibitor Genetics Study (HIGS), the Malmo International Brother Study (MIBS), and the Hemophilia Growth and Development Study (HGDS), was formed to conduct an association study to test the hypothesis that antibody development to FVIII is mediated by immune response and immune modifier genes. It was discovered that out of 14,626 25 SNPs from 1,081 genes including cytokines and their receptors, chemokines and their receptors, pathway genes involved in inflammatory and immune responses, and HLA genes, 329 SNPs were associated with FVIII inhibitor status. The 329 SNPs of the present invention are described herein, e.g. in Tables 1, 2, 3, and 4. The SNPs described herein can be used to predict the risk of an individual developing antibodies to FVIII. Predicting whether an individual is at risk of developing antibodies to FVIII, whether it is prior to the individual receiving FVIII therapy or once the individual has begun receiving FVIII therapy, is important because such a prediction makes it possible to adjust the dosage and/or timing of FVIII therapy provided to the individual,

WO 2011/131774

PCT/EP2011/056471 or to provide or adjust an alternative therapy such as bypass therapy, in order to avoid the individual developing antibodies to FVIII.

[0025] The present invention also relates to the discovery of strong SNP associations between inhibitor development and six markers within five genes. It was discovered that in the combined cohort, strong SNP associations with FVIII inhibitor status for the total group were observed in the D0CK2, MAPK9, F13A1, CD36, and PTPRR genes. A strong SNP association was found for the SNP rsl 1744216, a C>G variant in an intronic region of the D0CK2 gene (odds ratio or OR of 0.28 and a p-value or p of 0.00004); for the SNP rsl863993, a C>T variant in an intronic region of the DOCK2 gene (OR 3.9, p=Q.0002); for the SNP rs4147385, a C>T variant in an intronic region of the MAPK9 gene (OR 2.0, p=Q.0003); for the SNP rsl3206518, a T>C variant in an intronic region of the F13A1 gene (OR 0.32, p=Q.00007); for the SNP rs3211834, a A>C variant in an intronic region of the CD36 gene (OR 0.56, j>=0.0002); and for the SNP rsl567748, a A>C variant in an intronic region of the PTPRR gene (OR 0.51, p=Q.0003).

[0026] The six SNPs that were discovered to be strongly associated with inhibitor status are significant because they are located in genes that are implicated in processes of immune and/or inflammatory response and/or modulation. In some instances, the genes of the present invention are implicated in T cell development and/or T cell responsiveness. DOCK2, or Dedicator of cytokinesis 2, is specifically expressed in hematopoietic cells. It has been shown that DOCK2 regulates T cell responsiveness through immunological synapse formation and that DOCK2 is required in T cell precursors for the development of natural killer T cells, which are important for immune regulation and host defense against pathogens (Kunisaki et al., J. Immunol., 176:4640-4645 (2006)). MAPK9, also known as mitogen-activated protein kinase 9, Jun kinase 2, or stress activate protein kinase, is believed to play a key role in T cell differentiation. For example, mice deficient in Mapk9 exhibit disruption in CD4+ T cell differentiation, causing selective polarization of CD4+ T cells to the Th2 phenotype (Jaeschke et al., Proc. Natl. Acad. Sci. USA, 102:6931-6935 (2005); Rincon and Davis, Immunol. Rev., 228:212-224 (2009)). A balance between Thl cells (IL-1 and IFN-γ secreting cells that induce cellular immune response) and Th2 cells (IL-4, IL-5, and IL-10 secreting cells that downregulate the inflammatory activities of Thl) is critical for proper immune response, and in some autoimmune diseases there is a disruption of the Thl/Th2 balance. PTPRR, or protein tyrosine phosphatase receptor type R, is a signaling molecule that has been found to regulate MAP kinase activity, and therefore may also be implicated in regulating T cell differentiation by regulating MAPK9 activity.

WO 2011/131774

PCT/EP2011/056471 [0027] In some instances, the genes described herein are implicated in inflammatory response. CD36, or cluster of differentiation 36, is a class B scavenger receptor that has been shown to ^H regulate inflammatory signaling. For example, β-amyloid, a peptide associated with Alzheimer's disease, initiates a CD36-dependent pro-inflammatory signaling cascade in mononuclear cells (Moore et al., J. Biol. Chem., 277:47373-47379 (2002)), and CD36 is required a β-amyloidinduced CD36 upregulation of the inflammatory cytokine IL-Ιβ (El Khoury et al., J. Exp. Med., 197:1657-1666 (2003)).

[0028] In some instances, the genes described herein are implicated in the blood coagulation cascade. F13A1 encodes coagulation factor XIII (FXIII) A subunit. Upon FXIII activation by thrombin, activated FXIII acts on fibrin to form crosslinks between fibrin molecules as the final step in blood clot formation. SNPs in F13A1 have been reported to be associated with other aspects blood coagulation, specifically plasma fibrinogen concentration and fibrin clot porosity (Mannila et al., Thromb. Haemost., 95:420-427 (2006)).

[0029] The present invention also relates to the discovery of strong SNP associations between inhibitor development in patients with severe hemophilia and four markers within three genes. It was discovered that in the combined cohort, strong SNP associations with FVIII inhibitor status for the subgroup with severe hemophilia were observed in the DOCK2, MAPK9, and CD36 genes. For this subgroup, a strong association with inhibitor development was found for the SNP rs4147385, a C>T variant in an intronic region of the MAPK9 gene (OR 2.3, />=0.00003); for the

SNP rsi 1744216, a C>G variant in an intronic region of the DOCK2 gene (OR 0.30, />=0.00008); for the SNP rsi863993, a C>T variant in an intronic region of the DOCK2 gene (OR 4.4, />=0.0009); and for the SNP rs3211834, a A>C variant in an intronic region of the CD36 gene (OR 0.59,//=0.0008).

[0030] In one aspect, the present invention provides a method for predicting the risk of an individual developing antibodies to factor VIII (FVIII), the method comprising the steps of identifying at least one single nucleotide polymorphism (SNP) selected from the group consisting of the SNPs listed in Table 1, and predicting the risk of the individual of developing antibodies to FVIII.

[0031] In one embodiment, the SNP is located in a gene selected from the group consisting of

DOCK2, MAPK9, F13A1, CD36, and PTPRR. In one embodiment, the SNP is selected from the group consisting of rsi 1744216, rsl3206518, rs3211834, rsl863993, rs4147385, and rsl567748.

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 [0032] In one embodiment, the method further comprises the steps of amplifying genomic DNA of the individual using oligonucleotide primers that amplify the SNP selected from the group consisting of the SNPS listed in Table 1, and identifying the nucleotides present at the SNP.

[0033] In one embodiment, the individual has not yet received FVIII therapy. In one embodiment, the individual has received FVIII therapy. In one embodiment, the prediction allows for adjusting a dosage of FVIII therapy received by the individual. In one embodiment, the prediction allows for providing or adjusting a dosage of bypass therapy received by the individual.

[0034] In one embodiment, the individual has severe hemophilia. In one embodiment, the individual has severe hemophilia and the SNP is located in a gene selected from the group consisting of DOCK2, MAPK9, and CD36. In one embodiment, the individual has severe hemophilia and the SNP is selected from the group consisting of rsi 1744216, rsl863993, rs4147385, andrs3211834.

[0035] In one embodiment, the method further comprises the steps of analyzing a sample from the individual with an assay that specifically detects the SNP selected from the group consisting of the SNPs listed in Table 1, and identifying the nucleotides present at the SNP. In one embodiment, the assay or step of identification comprises a technique selected from the group consisting of mass spectroscopy, RT-PCR, microarray hybridization, pyro sequencing, thermal cycle sequencing, capillary array sequencing, and solid phase sequencing. In one embodiment, the assay comprises microarray hybridization.

[0036] In another aspect, the present invention provides an oligonucleotide from 10 to 60 nucleotides in length that contacts at least one single nucleotide polymorphism (SNP) selected from the group consisting of the SNPs listed in Table 1. In one embodiment, the oligonucleotide 25 contacts a SNP located in a gene selected from the group consisting of DOCK2, MAPK9, F13A1,

CD36, and PTPRR. In one embodiment, the oligonucleotide contacts a SNP selected from the group consisting of rsi 1744216, rsl3206518, rs3211834, rsl863993, rs4147385, and rsl567748. In one embodiment, the oligonucleotide is used to predict the risk of an individual developing antibodies to factor VIII (FVIII) and to adjust a dosage of FVIII therapy received by the individual. In one embodiment, the oligonucleotide is used to provide or adjust a dosage of bypass therapy received by the individual.

WO 2011/131774

PCT/EP2011/056471 [0037] In another aspect, the present invention provides a diagnostic kit comprising oligonucleotides to detect at least one single nucleotide polymorphism (SNP) selected from the ^H group consisting of the SNPs listed in Table 1. In one embodiment, the kit comprises oligonucleotides that detect a SNP located in a gene selected from the group consisting of

DOCK2, MAPK9, F13A1, CD36, and PTPRR. In one embodiment, the kit comprises oligonucleotides that detect a SNP selected from the group consisting of rsl 1744216, rs 13206518, rs3211834, rsl863993, rs4147385, and rs 1567748. In one embodiment, the kit is used to predict the risk of an individual developing antibodies to factor VIII (FVIII) and to adjust a dosage of FVIII therapy received by the individual. In one embodiment, the kit is used to provide or adjust a dosage of bypass therapy received by the individual.

[0038] In yet another aspect, the present invention provides a microarray comprising a support having a plurality of discrete regions, each discrete region having a nucleic acid fragment spotted thereon, wherein the nucleic acid fragment comprises a sequence that is complementary to a single nucleotide polymorphism (SNP) selected from the group consisting of the SNPs listed in

Table 1. In one embodiment, the microarray is used to predict the risk of an individual developing antibodies to factor VIII (FVIII) and to adjust a dosage of FVIII therapy received by the individual. In one embodiment, the microarray is used to provide or adjust a dosage of bypass therapy received by the individual.

[0039] In still another aspect, the present invention provides an isolated nucleic acid comprising a single nucleotide polymorphism (SNP) selected from the group consisting of the SNPs listed in Table 1. In one embodiment, the SNP is located in a gene selected from the group consisting of DOCK2, MAPK9, F13A1, CD36, and PTPRR. In one embodiment, the SNP is selected from the group consisting of rsll744216, rsl3206518, rs3211834, rsl863993, rs4147385, and rsl567748.

[0040] The present invention may be understood more readily by reference to the following detailed description of specific embodiments and the Examples included therein.

II. Definitions [0041] As used herein, the following terms have the meanings ascribed to them unless specified otherwise.

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 [0042] As used herein, the term factor VIII or FVIII refers to any form of factor VIII molecule with the typical characteristics of blood coagulation factor VIII, whether derived from blood plasma or produced through the use of recombinant DNA techniques, and including all modified forms of factor VIII. Factor VIII (FVIII) exists naturally and in therapeutic preparations as a heterogeneous distribution of polypeptides arising from a single gene product (see, e.g., Andersson et al., Proc. Natl. Acad. Sci. USA, 83:2979-2983 (1986)). Commercially available examples of therapeutic preparations containing Factor VIII include those sold under the trade names of HEMOFIF M, ADVATE, and RECOMBINATE (available from Baxter Healthcare Corporation, Deerfield, Ill., U.S.A.).

[0043] As used herein, the term inhibitory antibodies to factor VIII refers to antibodies that decrease or neutralize the procoagulant function of factor VIII. Inhibitory antibodies to factor VIII may develop in individuals who are not hemophiliacs, or they may develop in individuals with mild, moderate, or severe hemophilia. An individual may develop inhibitory antibodies to factor VIII prior to receiving any factor VIII therapy, or an individual may develop inhibitory antibodies to factor VIII after the onset of factor VIII therapy. In an individual receiving factor VIII therapy, inhibitory antibodies to factor VIII often appear early in the course of therapy, typically after about 9 to 11 exposure days, but sometimes develop sooner or later than 9 to 11 exposure days, within about 100 exposure days, and may develop at any time after the onset of factor VIII therapy.

[0044] As used herein, the term single nucleotide polymorphism or SNP refers to the occurrence of two or more genetically determined alternative genotypes in a population. A SNP can occur in a coding (i.e. gene) region of the genome, including the promoter region, untranslated 5' and 3' regions, introns, and coding regions found in the mRNA, or alternatively can occur in a noncoding region of the genome. In some embodiments, the SNPs associated with 25 gene sequences of the invention may be located within 300,000; 200,000; 100,000; 75,000;

50,000; or 10,000 base pairs from the gene sequence. SNP analysis is useful for detecting differences between polynucleotide sequences, such as the sequences identified in Table 1, that are associated with increased risk of developing a disease or condition, such as developing inhibitory antibodies to FVIII. These polynucleotide sequences may occur in or near any of the 30 genes listed in Table 1, including for example DOCK2, MAPK9, F13A1, CD36, and PTPRR.

The SNPs of the present invention are useful, for instance, for predicting the risk of developing inhibitory antibodies to FVIII. For example, if an individual carries at least one SNP linked to a

WO 2011/131774

PCT/EP2011/056471 disease-associated allele of the gene sequences of the invention, the individual is likely at increased risk for developing inhibitory antibodies to FVIII.

[0045] It will be understood by the skilled artisan that SNPs may be used singly or in combination with other SNPs for any of the uses, e.g., predicting the risk of developing inhibitory antibodies to FVIII, disclosed herein.

[0046] As used herein, the term gene refers to the segment of DNA involved in producing a polypeptide chain; it includes regions preceding and following the coding region, such as the promoter and 3’-untranslated region, respectively, as well as intervening sequences (introns) between individual coding segments (exons).

[0047] As used herein, the term oligonucleotide refers to a nucleic acid sequence of approximately 5 nucleotides or greater in length, and up to as many as approximately 100 nucleotides in length, which can be used as a primer, probe, or amplimer. Oligonucleotides are often between about 10 and about 50 nucleotides in length, more often between about 10 and about 40 nucleotides, very often between about 15 and about 30 nucleotides, and the terms oligonucleotides or oligomers can also refer to synthetic and/or non-naturally occurring nucleic acids (i.e., comprising nucleic acid analogues or modified backbone residues or linkages) [0048] As used herein, the term nucleic acid refers to deoxyribonucleotides or ribonucleotides and polymers thereof in either single- or double-stranded form, and complements thereof. The term encompasses nucleic acids containing known nucleotide analogs or modified backbone residues or linkages, which are synthetic, naturally occurring, and non-naturally occurring, which have similar binding properties as the reference nucleic acid, and which are metabolized in a manner similar to the reference nucleotides. Examples of such analogs include, without limitation, phosphorothioates, phosphoramidates, methyl phosphonates, chiral-methyl phosphonates, 2-O-methyl ribonucleotides, and peptide-nucleic acids (PNAs).

[0049] For PCR, a temperature of about 36°C is typical for low stringency amplification, although annealing temperatures may vary between about 32°C and 48°C depending on primer length. For high stringency PCR amplification, a temperature of about 62°C is typical, although high stringency annealing temperatures can range from about 50°C to about 65°C, depending on the primer length and specificity. Typical cycle conditions for both high and low stringency amplifications include a denaturation phase of 90°C - 95°C for 30 sec - 2 min., an annealing phase lasting 30 sec. - 2 min., and an extension phase of about 72°C for 1-2 min. Protocols and

WO 2011/131774

PCT/EP2011/056471 guidelines for low and high stringency amplification reactions are provided, e.g., in Innis et al. (1990) PCR Protocols, A Guide to Methods and Applications, Academic Press, Inc. N.Y.).ash ^H conditions can be utilized to provide conditions of similar stringency.

[0050] As used herein, the term sample includes extractions of nucleic acid such as DNA, sections of tissues such as biopsy and autopsy samples, and frozen sections taken for histological purposes. Such samples include blood and blood fractions or products (e.g., serum, buffy coat, plasma, platelets, red blood cells, and the like), sputum, cheek cells tissue, cultured cells (e.g., primary cultures, explants, and transformed cells), stool, urine, other biological fluids (e.g., prostatic fluid, gastric fluid, intestinal fluid, renal fluid, lung fluid, cerebrospinal fluid, and the like), etc. A sample is typically obtained from a subject such as a eukaryotic organism, most preferably a mammal such as a primate, e.g., chimpanzee or human; cow; dog; cat; a rodent, e.g., guinea pig, rat, mouse; rabbit; or a bird; reptile; or fish.

[0051] As used herein, the terms hemophilia or haemophilia refer to a group of disease states broadly characterized by reduced blood clotting or coagulation. Hemophilia may refer to

Type A, Type B, or Type C hemophilia, or to the composite of all three diseases types. Type A hemophilia (hemophilia A) is caused by a reduction or loss of factor VIII (FVIII) activity and is the most prominent of the hemophilia subtypes. Type B hemophilia (hemophilia B) results from the loss or reduction of factor IX (FIX) clotting function. Type C hemophilia (hemophilia C) is a consequence of the loss or reduction in factor XI (FXI) clotting activity. Hemophilia A and B are X-linked diseases, while hemophilia C is autosomal. Common treatments for hemophilia include both prophylactic and on-demand administration of clotting factors, such as FVIII, FIX, including Bebulin®-VH, and FXI, as well as FEIBA-VH, desmopressin, and plasma infusions.

[0052] As used herein, the term FVIII therapy includes any therapeutic approach of providing factor VIII to a patient to relieve, diminish, or prevent the reoccurrence of one or more symptoms (i.e., clinical factors) associated with hemophilia. The term encompasses administering any compound, drug, procedure, or regimen comprising factor VIII, including any modified form of factor VIII, which is useful for maintaining or improving the health of an individual with hemophilia and includes any of the therapeutic agents described herein. One skilled in the art will appreciate that either the course of FVIII therapy or the dose of FVIII therapy can be changed, e.g., based upon the results obtained in accordance with the present invention.

WO 2011/131774

PCT/EP2011/056471 [0053] As used herein, the term bypass therapy includes any therapeutic approach of providing non-factor VIII hemostatic agents, compounds or coagulation factors to a patient to ^H relieve, diminish, or prevent the reoccurrence of one or more symptoms (i.e., clinical factors) associated with hemophilia. Non-FVIII compounds and coagulation factors that may be provided include, but are not limited to, Factor VIII Inhibitor Bypass Activity (FEIBA), recombinant activated factor VII (FVIIa), prothrombin complex concentrates, and activated prothrombin complex concentrates. These non-FVIII compounds and coagulation factors may be recombinant or plasma-derived. One skilled in the art will appreciate that either the course of bypass therapy or the dose of bypass therapy can be changed, e.g., based upon the results obtained in accordance with the present invention.

[0054] As used herein, a “combination therapy comprising administration of FVIII and a FVIII bypass agent” includes any therapeutic approach of providing both Factor VIII and a non-Factor VIII hemostatic agent to a patient to relieve, diminish, or prevent the reoccurrence of one or more symptoms (i.e., clinical factors) associated with hemophilia. The term encompasses administering any compound, drug, procedure, or regimen comprising factor VIII, including any modified form of factor VIII, which is useful for maintaining or improving the health of an individual with hemophilia and includes any of the therapeutic agents described herein. NonFVIII compounds and coagulation factors that may be provided include, but are not limited to, Factor VIII Inhibitor Bypass Activity (FEIBA), recombinant activated factor VII (FVIIa), prothrombin complex concentrates, and activated prothrombin complex concentrates. The Factor VIII and non-Factor VIII compounds and coagulation factors may be recombinant or plasma-derived.

[0055] In one embodiment, combination therapy may refer to administration of Factor VIII and a non-FVIII hemostatic agent in a single therapeutic dose. In another embodiment, combination 25 therapy may refer to administration of Factor VIII and a non-FVIII hemostatic agent in separate therapeutic doses. For example, Factor VIII and a non-FVIII hemostatic agent may be administered in separate doses received according to a single dosage schedule, or alternatively in separate doses received according to separate dosing schedules. In one embodiment, the dosing schedules for the Factor VIII and the non-FVIII hemostatic agent may be concurrent or alternating (i.e., overlapping). In another embodiments, the dosing schedules may be nonoverlapping (i.e., where one dosing regime is completed before beginning a second dosing regime with the alternate therapy). One skilled in the art will appreciate that either the course

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 and/or dose of FVIII therapy and/or non-FVIII hemostatic agent (i.e., FVIII bypass agent) can be changed, e.g., based upon the results obtained in accordance with the present invention. In one embodiment, the identification of SNPs corresponding to one or more SNPs found in Tables 1 to 4, in a sample from a patient diagnosed with Hemophilia, will allow one of skill in the art to tailor the combination therapy (i.e., increase or decrease the regime and/or dose of one or both of the Factor VIII and FVIII bypass agent) to the individual, based on the individuals risk of developing Factor VIII inhibitors.

[0056] The terms therapeutically effective amount or dose or therapeutically sufficient amount or dose or effective or sufficient amount or dose refer to a dose that produces therapeutic effects for which it is administered. For example, a therapeutically effective amount of a drug useful for treating hemophilia can be the amount that is capable of preventing or relieving one or more symptoms associated with hemophilia. The exact dose will depend on the purpose of the treatment, and will be ascertainable by one skilled in the art using known techniques (see, e.g., Lieberman, Pharmaceutical Dosage Forms (vols. 1-3, 1992); Lloyd, The

Art, Science and Technology of Pharmaceutical Compounding (1999); Pickar, Dosage Calculations (1999); and Remington: The Science and Practice of Pharmacy, 20th Edition, 2003, Gennaro, Ed., Lippincott, Williams & Wilkins).

[0057] As used herein, an “increased risk” of developing antibodies against Factor VIII refers to an increased probability or increased likelihood that an individual will develop antibodies 0 against Factor VIII, for example, in response to treatment comprising administration of Factor

VIII. In one embodiment, the increased risk is in comparison with an average risk of developing

Factor VIII inhibitors in a given Hemophilia A population (e.g., the average risk ascribed to an individual for which SNP genotyping has not been performed. In certain embodiments, an increased risk will correspond to at least a 5% increased risk. In another embodiment, an increased risk will correspond to at least a 10% increased risk, increased risk will correspond to at least a 25% increased risk, increased risk will correspond to at least a 50% increased risk, increased risk will correspond to at least a 75% increased risk, increased risk will correspond to at least a 100% increased risk. In another embodiment, increased risk will correspond to at least a 150% increased risk. In another embodiment, increased risk will correspond to at least a 200% increased risk. In another embodiment, increased risk will correspond to at least a 250% increased risk. In another embodiment,

In another embodiment,

In another embodiment,

In another embodiment,

In another embodiment, an an an an an an an an

WO 2011/131774

PCT/EP2011/056471 increased risk will correspond to at least a 300% increased risk. In yet other embodiments, an increased risk will correspond to at least a 5% increased risk, or at least a 10%, 15%, 20%, 25%, ^H 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%,

250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%,

380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, 500%,

525%, 550%, 575%, 600%, 625%, 650%, 675%, 700%, 750%, 800%, 850%, 900%, 950%,

1000%, or greater increased risk.

[0058] As used herein, a “decreased risk” of developing antibodies against Factor VIII refers to a decreased probability or decreased likelihood that a individual will develop antibodies against Factor VIII, for example, in response to treatment comprising administration of Factor VIII. In one embodiment, the decreased risk is in comparison with a average risk of developing Factor VIII inhibitors in a given Hemophilia A population (e.g., the average risk ascribed to a individual for which SNP genotyping has not been performed). In certain embodiments, a decreased risk will correspond to at least a 5% decreased risk. In another embodiment, a decreased risk will correspond to at least a 10% decreased risk. In another embodiment, a decreased risk will correspond to at least a 25% decreased risk. In another embodiment, a decreased risk will correspond to at least a 50% decreased risk. In another embodiment, a decreased risk will correspond to at least a 75% decreased risk. In another embodiment, a decreased risk will correspond to at least a 100% decreased risk. In another embodiment, a decreased risk will correspond to at least a 150% decreased risk. In another embodiment, a decreased risk will correspond to at least a 200% decreased risk. In another embodiment, a decreased risk will correspond to at least a 250% decreased risk. In another embodiment, a decreased risk will correspond to at least a 300% decreased risk. In yet other embodiments, a decreased risk will correspond to at least a 5% decreased risk, or at least a 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 110%, 120%, 130%, 140%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240%,

250%, 260%, 270%, 280%, 290%, 300%, 310%, 320%, 330%, 340%, 350%, 360%, 370%,

380%, 390%, 400%, 410%, 420%, 430%, 440%, 450%, 460%, 470%, 480%, 490%, 500%,

525%, 550%, 575%, 600%, 625%, 650%, 675%, 700%, 750%, 800%, 850%, 900%, 950%,

1000%, or greater decreased risk.

WO 2011/131774

PCT/EP2011/056471

III. Predictive Methods and Assays _H [0059] In certain aspects, the present invention provides methods for predicting the risk of an individual developing antibodies to factor VIII (FVIII). Risk prediction involves identifying at least one single nucleotide polymorphism (SNP) selected from the group consisting of the SNPs listed in Table 1, and on the basis of the nucleotides present at the SNP, determining whether the individual is more likely to develop antibodies to FVIII or not. SNP analysis is useful for detecting differences between alleles of the polynucleotides (e.g., genes) of the invention. For example, if an individual carries at least one SNP linked to a disease or condition-associated allele of the gene sequences of the invention, the individual is likely at an increased risk of developing antibodies to FVIII. In some embodiments, the SNP associated with the gene sequences of the invention is located within 300,000; 200,000; 100,000; 75,000; 50,000; or 10,000 base pairs from the gene sequence.

[0060] Predicting the risk of an individual developing antibodies to FVIII may be performed when the individual has not received any FVIII therapy. Alternatively, risk prediction may be performed soon after the individual begins receiving FVIII therapy. Alternatively, risk prediction may be performed at any time when there are suspected symptoms of FVIII antibody development in the individual. One of skill in the art will be able to identify symptoms of FVIII antibody development in the individual.

[0061] In some embodiments, the present invention provides methods of predicting the risk of 0 an individual developing antibodies to FVIII comprising identifying a SNP located in a gene selected from the group consisting of DOCK2, MAPK9, F13A1, CD36, and PTPRR. In one embodiment, the method comprises identifying the SNP rsl 1744216 and determining whether the individual has a C>G polymorphism that is associated with increased risk of developing antibodies to FVIII. In one embodiment, the method comprises identifying the SNP rsl3206518 and determining whether the individual has a T>C polymorphism that is associated with increased risk of developing antibodies to FVIII. In one embodiment, the method comprises identifying the SNP rs3211834 and determining whether the individual has a A>C polymorphism that is associated with increased risk of developing antibodies to FVIII. In one embodiment, the method comprises identifying the SNP rsl863993 and determining whether the individual has a C>T polymorphism that is associated with increased risk of developing antibodies to FVIII. In one embodiment, the method comprises identifying the SNP rs4147385

WO 2011/131774

PCT/EP2011/056471 and determining whether the individual has a C>T polymorphism that is associated with increased risk of developing antibodies to FVIII. In one embodiment, the method comprises ^H identifying the SNP rsl567748 and determining whether the individual has a A>C polymorphism that is associated with increased risk of developing antibodies to FVIII.

[0062] The predictive methods of the present invention may also be used to determine how to provide or adjust a dosage of therapy received by the individual. In some embodiments, the identification of a variant or condition-associated genotype for a SNP selected from the SNPs listed in Table 1 allows for adjusting a dosage of FVIII therapy received by the individual. In some embodiments, the identification of a variant or condition-associated genotype for a SNP selected from the SNPs listed in Table 1 allows for providing or adjusting a dosage of bypass therapy received by the individual.

[0063] In some embodiments of the present invention, the individual for whom the risk prediction is desired may be an individual who has severe hemophilia. In some embodiments wherein the individual for whom the risk prediction is desired has severe hemophilia, the SNP to 5 be identified may be located in a gene selected from the group consisting of DOCK2, MAPK9, and CD36 (Table 2). In one embodiment, the individual has severe hemophilia and the method comprises identifying the SNP rsi 1744216 and determining whether the individual has a C>G polymorphism that is associated with increased risk of developing antibodies to FVIII. In one embodiment, the individual has severe hemophilia and the method comprises identifying the 0 SNP rsi863993 and determining whether the individual has a C>T polymorphism that is associated with increased risk of developing antibodies to FVIII. In one embodiment, the individual has severe hemophilia and the method comprises identifying the SNP rs4147385 and determining whether the individual has a C>T polymorphism that is associated with increased risk of developing antibodies to FVIII. In one embodiment, the individual has severe hemophilia 25 and the method comprises identifying the SNP rs3211834 and determining whether the individual has a A>C polymorphism that is associated with increased risk of developing antibodies to FVIII.

[0064] The genotype of the SNP of interest in the individual may be measured by taking a blood, saliva, urine, or other tissue sample containing nucleic acid, e.g., DNA, from the individual and analyzing the sample with an assay that specifically detects the presence of the SNP of interest. Alternatively, the genotype of the SNP of interest in the individual may be

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 measured by taking a blood, saliva, urine, or other tissue sample from the individual and amplifying the genomic DNA of the sample using oligonucleotide primers that amplify the SNP of interest.

A. Methods for Predicting Risk in Hemophilia Patients [0065] In one aspect, the present invention provides methods for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia A by detecting the presence of one or more of the SNPs identified herein. In one embodiment, the method comprises the steps of detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed 0 in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4, in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII.

[0066] Generally, the predicted risk associated with each SNP is relative to the Odds ratio (OR) calculated for that particular SNP. Therefore, the detection of a SNP with an OR less than one is generally associated with a reduced likelihood (i.e., a reduced risk) of the individual developing antibodies against Factor VIII. Likewise, the detection of a SNP with an OR greater than one is generally associated with an increased likelihood (i.e., a reduced risk) of the individual developing antibodies against Factor VIII. Accordingly, treatment can then be assigned and/or administered to an individual diagnosed with Hemophilia A appropriately based on the relative risk of the individual developing antibodies against Factor VIII.

1. Individuals Diagnosed with Hemophilia A [0067] In one embodiment, the present invention provides a method for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia A the method comprising the steps of detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed 25 in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4, in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII.

[0068] In one embodiment of the method, the individual has been diagnosed with mild Hemophilia. In another embodiment, the individual has been diagnosed with moderate Hemophilia. In yet another embodiment, the individual has been diagnosed with severe 30 Hemophilia.

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 [0069] In one embodiment of the method, the step of detecting the presence of at least one SNP comprises amplifying a nucleic acid present in the biological sample. In another embodiment, the step of detecting the presence of at least one SNP comprises a technique selected from the group consisting of mass spectroscopy, RT-PCR, microarray hybridization, 5 pyrosequencing, thermal cycle sequencing, capillary array sequencing, solid phase sequencing, a hybridization-based method, an enzymatic-based method, a PCR-based method, a sequencing method, a ssDNA conformational method, and a DNA melting temperature assay.

[0070] In one embodiment, the method further comprises assigning and/or administering a treatment to the individual based on the predicted risk of developing antibodies against Factor 0 VIII. In a specific embodiment, treatment comprising administration of Factor VIII is assigned to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, treatment comprising Factor VIII bypass therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0071] In yet another specific embodiment, combination therapy comprising administration of 5 Factor VIII and a FVIII bypass agent is assigned to an individual based on the predicted risk of developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is assigned to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, a combination therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0072] In one embodiment, treatment comprising administration of Factor VIII is provided to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, treatment comprising Factor VIII bypass therapy is provided to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0073] In yet another embodiment, combination therapy comprising administration of Factor 25 VIII and a FVIII bypass agent is provided to an individual based on the predicted risk of developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is provided to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, a combination therapy is provided to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0074] In one embodiment, the method further comprises adjusting a dosage of a treatment comprising administration of Factor VIII to the individual based on the predicted risk of

WO 2011/131774

PCT/EP2011/056471 developing antibodies against Factor VIII. In a specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted decreased risk of developing antibodies against ^H Factor VIII is increased. In another specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted increased risk of developing antibodies against

Factor VIII is decreased.

[0075] In another embodiment, the method further comprises adjusting the dosage and/or frequency of Factor VIII administration in a combination therapy based on the predicted risk of developing antibodies against FVIII. In one embodiment, the method comprises increasing the dosage or frequency of Factor VIII administered in a combination therapy to an individual with a 0 predicted decreased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or frequency of Factor VIII administered in a combination therapy to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0076] In another embodiment, the method further comprises adjusting the dosage and/or frequency of a non-FVIII hemostatic agent administered in a combination therapy based on the predicted risk of developing antibodies against FVIII. In one embodiment, the method comprises increasing the dosage or frequency of a non-FVIII hemostatic agent administered in a combination therapy to an individual with a predicted increased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or frequency of a non-FVIII hemostatic agent administered in a combination therapy to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0077] In another embodiment, the method further comprises adjusting the dosage and/or frequency of both Factor VIII and a non-FVIII hemostatic agent administered in a combination therapy based on the predicted risk of developing antibodies against FVIII. In this fashion, a 25 combination therapy may be optimized for an individual with a specific predicted risk of developing antibodies against FVIII. Optimization of the dosage and/or frequency of Factor VIII and non-FVIII hemostatic agents in combination therapy may be achieved by any combination of increasing the frequency of FVIII administration, decreasing the frequency of FVIII administration, increasing the dosage of FVIII, decreasing the dosage of FVIII, increasing the frequency of non-FVIII hemostatic agent administration, decreasing the frequency of non-FVIII

WO 2011/131774

PCT/EP2011/056471 hemostatic agent administration, increasing the dosage of a non-FVIII hemostatic agent, and decreasing the dosage of a non-FVIII hemostatic agent.

[0078] In a specific embodiment, the method comprises increasing the frequency and/or dosage of FVIII and decreasing the frequency and/or dosage of a non-FVIII hemostatic agent administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0079] In another specific embodiment, the method comprises decreasing the frequency and/or dosage of FVIII and increasing the frequency and/or dosage of a non-FVIII hemostatic agent administered to an individual with a predicted increased risk of developing antibodies against

Factor VIII.

[0080] In a preferred embodiment, the method comprises the detection of at least one SNP selected from those listed in Table 3. In a specific embodiment, the method comprises the detection of at least on SNP selected from the group consisting of rsl2368829, rsl 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712. In one embodiment, at least one detected SNP is rsl2368829. In another embodiment, at least one detected SNP is rsl 1744216. In another embodiment, at least one detected SNP is rsl863993. In another embodiment, at least one detected SNP is rs4147385. In another embodiment, at least one detected SNP is rs 12546235. In another embodiment, at least one detected SNP is rs4242389. In another embodiment, at least one detected SNP is rsl0054825. In another embodiment, at least one detected SNP is rsl7535213. In another embodiment, at least one detected SNP is rsl0072056. In another embodiment, at least one detected SNP is rs 17725712.

a) Prior to Factor VIII Therapy [0081] In one embodiment, the present invention relates specifically to an individual or group of individuals diagnosed with Hemophilia A that have not previously received Factor VIII therapy (i.e., not received treatment comprising administration of Factor VIII).

[0082] In one embodiment, a method is provided for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia A, who has not previously received treatment comprising administration of FVIII, comprising detecting the 30 presence of at least one single nucleotide polymorphism (SNP) selected from the group

WO 2011/131774

PCT/EP2011/056471 consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4, in a biological sample from the individual; and predicting the risk of the ^H individual of developing antibodies to FVIII.

[0083] In one embodiment of the method, the individual has been diagnosed with mild

Hemophilia. In another embodiment, the individual has been diagnosed with moderate Hemophilia. In yet another embodiment, the individual has been diagnosed with severe Hemophilia.

[0084] In one embodiment of the method, the step of detecting the presence of at least one SNP comprises amplifying a nucleic acid present in the biological sample. In another embodiment, the step of detecting the presence of at least one SNP comprises a technique selected from the group consisting of mass spectroscopy, RT-PCR, microarray hybridization, pyrosequencing, thermal cycle sequencing, capillary array sequencing, solid phase sequencing, a hybridization-based method, an enzymatic-based method, a PCR-based method, a sequencing method, a ssDNA conformational method, and a DNA melting temperature assay.

[0085] In one embodiment, the method further comprises assigning and/or administering a treatment to the individual based on the predicted risk of developing antibodies against Factor VIII. In a specific embodiment, treatment comprising administration of Factor VIII is assigned to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, treatment comprising Factor VIII bypass therapy is assigned to an 0 individual with a predicted increased risk of developing antibodies against Factor VIII.

[0086] In yet another specific embodiment, combination therapy comprising administration of Factor VIII and a FVIII bypass agent is assigned to an individual based on the predicted risk of developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is assigned to an individual with a predicted decreased risk of developing antibodies against Factor 25 VIII. In another specific embodiment, a combination therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0087] In one embodiment, treatment comprising administration of Factor VIII is provided to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, treatment comprising Factor VIII bypass therapy is provided to an 30 individual with a predicted increased risk of developing antibodies against Factor VIII.

WO 2011/131774

PCT/EP2011/056471 [0088] In yet another embodiment, combination therapy comprising administration of Factor VIII and a FVIII bypass agent is provided to an individual based on the predicted risk of ^H developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is provided to an individual with a predicted decreased risk of developing antibodies against Factor

VIII. In another specific embodiment, a combination therapy is provided to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0089] In one embodiment, the method further comprises adjusting a dosage of a treatment comprising administration of Factor VIII to the individual based on the predicted risk of developing antibodies against Factor VIII. In a specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII is increased. In another specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted increased risk of developing antibodies against Factor VIII is decreased.

[0090] In another embodiment, the method further comprises adjusting the dosage and/or frequency of Factor VIII administration in a combination therapy based on the predicted risk of developing antibodies against FVIII. In one embodiment, the method comprises increasing the dosage or frequency of Factor VIII administered in a combination therapy to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or frequency of Factor VIII administered in a combination therapy to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0091] In another embodiment, the method further comprises adjusting the dosage and/or frequency of a non-FVIII hemostatic agent administered in a combination therapy based on the predicted risk of developing antibodies against FVIII. In one embodiment, the method comprises increasing the dosage or frequency of a non-FVIII hemostatic agent administered in a combination therapy to an individual with a predicted increased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or frequency of a non-FVIII hemostatic agent administered in a combination therapy to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0092] In another embodiment, the method further comprises adjusting the dosage and/or frequency of both Factor VIII and a non-FVIII hemostatic agent administered in a combination

WO 2011/131774

PCT/EP2011/056471 therapy based on the predicted risk of developing antibodies against FVIII. In this fashion, a combination therapy may be optimized for an individual with a specific predicted risk of ^H developing antibodies against FVIII. Optimization of the dosage and/or frequency of Factor VIII and non-FVIII hemostatic agents in combination therapy may be achieved by any combination of increasing the frequency of FVIII administration, decreasing the frequency of FVIII administration, increasing the dosage of FVIII, decreasing the dosage of FVIII, increasing the frequency of non-FVIII hemostatic agent administration, decreasing the frequency of non-FVIII hemostatic agent administration, increasing the dosage of a non-FVIII hemostatic agent, and decreasing the dosage of a non-FVIII hemostatic agent.

[0093] In a specific embodiment, the method comprises increasing the frequency and/or dosage of FVIII and decreasing the frequency and/or dosage of a non-FVIII hemostatic agent administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0094] In another specific embodiment, the method comprises decreasing the frequency and/or dosage of FVIII and increasing the frequency and/or dosage of a non-FVIII hemostatic agent administered to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0095] In a preferred embodiment, the method comprises the detection of at least one SNP selected from those listed in Table 3. In a specific embodiment, the method comprises the detection of at least on SNP selected from the group consisting of rsl2368829, rsi 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712. In one embodiment, at least one detected SNP is rsl2368829. In another embodiment, at least one detected SNP is rsi 1744216. In another embodiment, at least one detected SNP is rsl863993. In another embodiment, at least one detected SNP is rs4147385. In 25 another embodiment, at least one detected SNP is rsl2546235. In another embodiment, at least one detected SNP is rs4242389. In another embodiment, at least one detected SNP is rsl0054825. In another embodiment, at least one detected SNP is rsl7535213. In another embodiment, at least one detected SNP is rsl0072056. In another embodiment, at least one detected SNP is rs 17725712.

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

b) After Initial Factor VIII Therapy [0096] In one embodiment, the present invention relates specifically to an individual or group of individuals diagnosed with Hemophilia A that have previously received Factor VIII therapy (z.e., received treatment comprising administration of Factor VIII).

[0097] In one embodiment, a method is provided for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia A, who has previously received treatment comprising administration of FVIII, comprising detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4, in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII.

[0098] In one embodiment of the method, the individual has been diagnosed with mild Hemophilia. In another embodiment, the individual has been diagnosed with moderate Hemophilia. In yet another embodiment, the individual has been diagnosed with severe

Hemophilia.

[0099] In one embodiment of the method, the step of detecting the presence of at least one SNP comprises amplifying a nucleic acid present in the biological sample. In another embodiment, the step of detecting the presence of at least one SNP comprises a technique selected from the group consisting of mass spectroscopy, RT-PCR, microarray hybridization, pyrosequencing, thermal cycle sequencing, capillary array sequencing, solid phase sequencing, a hybridization-based method, an enzymatic-based method, a PCR-based method, a sequencing method, a ssDNA conformational method, and a DNA melting temperature assay.

[0100] In one embodiment, the method further comprises assigning and/or administering a treatment to the individual based on the predicted risk of developing antibodies against Factor

VIII. In a specific embodiment, treatment comprising administration of Factor VIII is assigned to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, treatment comprising Factor VIII bypass therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0101] In yet another specific embodiment, combination therapy comprising administration of

Factor VIII and a FVIII bypass agent is assigned to an individual based on the predicted risk of

WO 2011/131774

PCT/EP2011/056471 developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is assigned to an individual with a predicted decreased risk of developing antibodies against Factor ^H VIII. In another specific embodiment, a combination therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0102] In one embodiment, treatment comprising administration of Factor VIII is provided to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, treatment comprising Factor VIII bypass therapy is provided to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0103] In yet another embodiment, combination therapy comprising administration of Factor 0 VIII and a FVIII bypass agent is provided to an individual based on the predicted risk of developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is provided to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, a combination therapy is provided to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0104] In one embodiment, the method further comprises adjusting a dosage of a treatment comprising administration of Factor VIII to the individual based on the predicted risk of developing antibodies against Factor VIII. In a specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII is increased. In another specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted increased risk of developing antibodies against Factor VIII is decreased.

[0105] In another embodiment, the method further comprises adjusting the dosage and/or frequency of Factor VIII administration in a combination therapy based on the predicted risk of developing antibodies against FVIII. In one embodiment, the method comprises increasing the 25 dosage or frequency of Factor VIII administered in a combination therapy to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or frequency of Factor VIII administered in a combination therapy to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0106] In another embodiment, the method further comprises adjusting the dosage and/or frequency of a non-FVIII hemostatic agent administered in a combination therapy based on the

WO 2011/131774

PCT/EP2011/056471 predicted risk of developing antibodies against FVIII. In one embodiment, the method comprises increasing the dosage or frequency of a non-FVIII hemostatic agent administered in a ^H combination therapy to an individual with a predicted increased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or frequency of a non-FVIII hemostatic agent administered in a combination therapy to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0107] In another embodiment, the method further comprises adjusting the dosage and/or frequency of both Factor VIII and a non-FVIII hemostatic agent administered in a combination therapy based on the predicted risk of developing antibodies against FVIII. In this fashion, a combination therapy may be optimized for an individual with a specific predicted risk of developing antibodies against FVIII. Optimization of the dosage and/or frequency of Factor VIII and non-FVIII hemostatic agents in combination therapy may be achieved by any combination of increasing the frequency of FVIII administration, decreasing the frequency of FVIII administration, increasing the dosage of FVIII, decreasing the dosage of FVIII, increasing the frequency of non-FVIII hemostatic agent administration, decreasing the frequency of non-FVIII hemostatic agent administration, increasing the dosage of a non-FVIII hemostatic agent, and decreasing the dosage of a non-FVIII hemostatic agent.

[0108] In a specific embodiment, the method comprises increasing the frequency and/or dosage of FVIII and decreasing the frequency and/or dosage of a non-FVIII hemostatic agent administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0109] In another specific embodiment, the method comprises decreasing the frequency and/or dosage of FVIII and increasing the frequency and/or dosage of a non-FVIII hemostatic agent administered to an individual with a predicted increased risk of developing antibodies against

Factor VIII.

[0110] In a preferred embodiment, the method comprises the detection of at least one SNP selected from those listed in Table 3. In a specific embodiment, the method comprises the detection of at least on SNP selected from the group consisting of rsl2368829, rsi 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712. In one embodiment, at least one detected SNP is rsl2368829. In another embodiment, at least one detected SNP is rsi 1744216. In another embodiment, at least one

WO 2011/131774

PCT/EP2011/056471 detected SNP is rsl863993. In another embodiment, at least one detected SNP is rs4147385. In another embodiment, at least one detected SNP is rs 12546235. In another embodiment, at least ^H one detected SNP is rs4242389. In another embodiment, at least one detected SNP is rsl0054825. In another embodiment, at least one detected SNP is rsl7535213. In another embodiment, at least one detected SNP is rsl0072056. In another embodiment, at least one detected SNP is rs 17725712.

2. Individuals Diagnosed with Severe Hemophilia A [0111] In one embodiment, the present invention provides a method for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with severe

Hemophilia A, the method comprising the steps of detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4, in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII.

[0112] In one embodiment of the method, the step of detecting the presence of at least one

SNP comprises amplifying a nucleic acid present in the biological sample. In another embodiment, the step of detecting the presence of at least one SNP comprises a technique selected from the group consisting of mass spectroscopy, RT-PCR, microarray hybridization, pyrosequencing, thermal cycle sequencing, capillary array sequencing, solid phase sequencing, a hybridization-based method, an enzymatic-based method, a PCR-based method, a sequencing method, a ssDNA conformational method, and a DNA melting temperature assay.

[0113] In one embodiment, the method further comprises assigning and/or administering a treatment to the individual based on the predicted risk of developing antibodies against Factor VIII. In a specific embodiment, treatment comprising administration of Factor VIII is assigned to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In 25 another specific embodiment, treatment comprising Factor VIII bypass therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0114] In yet another specific embodiment, combination therapy comprising administration of Factor VIII and a FVIII bypass agent is assigned to an individual based on the predicted risk of developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is 30 assigned to an individual with a predicted decreased risk of developing antibodies against Factor

WO 2011/131774

PCT/EP2011/056471

VIII. In another specific embodiment, a combination therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0115] In one embodiment, treatment comprising administration of Factor VIII is provided to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, treatment comprising Factor VIII bypass therapy is provided to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0116] In yet another embodiment, combination therapy comprising administration of Factor VIII and a FVIII bypass agent is provided to an individual based on the predicted risk of developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is 0 provided to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, a combination therapy is provided to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0117] In one embodiment, the method further comprises adjusting a dosage of a treatment comprising administration of Factor VIII to the individual based on the predicted risk of developing antibodies against Factor VIII. In a specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII is increased. In another specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted increased risk of developing antibodies against Factor VIII is decreased.

[0118] In another embodiment, the method further comprises adjusting the dosage and/or frequency of Factor VIII administration in a combination therapy based on the predicted risk of developing antibodies against FVIII. In one embodiment, the method comprises increasing the dosage or frequency of Factor VIII administered in a combination therapy to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or frequency of Factor VIII administered in a combination therapy to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0119] In another embodiment, the method further comprises adjusting the dosage and/or frequency of a non-FVIII hemostatic agent administered in a combination therapy based on the 30 predicted risk of developing antibodies against FVIII. In one embodiment, the method comprises increasing the dosage or frequency of a non-FVIII hemostatic agent administered in a

WO 2011/131774

PCT/EP2011/056471 combination therapy to an individual with a predicted increased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or ^H frequency of a non-FVIII hemostatic agent administered in a combination therapy to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0120] In another embodiment, the method further comprises adjusting the dosage and/or frequency of both Factor VIII and a non-FVIII hemostatic agent administered in a combination therapy based on the predicted risk of developing antibodies against FVIII. In this fashion, a combination therapy may be optimized for an individual with a specific predicted risk of developing antibodies against FVIII. Optimization of the dosage and/or frequency of Factor VIII and non-FVIII hemostatic agents in combination therapy may be achieved by any combination of increasing the frequency of FVIII administration, decreasing the frequency of FVIII administration, increasing the dosage of FVIII, decreasing the dosage of FVIII, increasing the frequency of non-FVIII hemostatic agent administration, decreasing the frequency of non-FVIII hemostatic agent administration, increasing the dosage of a non-FVIII hemostatic agent, and decreasing the dosage of a non-FVIII hemostatic agent.

[0121] In a specific embodiment, the method comprises increasing the frequency and/or dosage of FVIII and decreasing the frequency and/or dosage of a non-FVIII hemostatic agent administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0122] In another specific embodiment, the method comprises decreasing the frequency and/or dosage of FVIII and increasing the frequency and/or dosage of a non-FVIII hemostatic agent administered to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0123] In a preferred embodiment, the method comprises the detection of at least one SNP selected from those listed in Table 4. In a specific embodiment, the method comprises the detection of at least on SNP selected from the group consisting of rsl2368829, rs4147385, rsl 1744216, rs 1863993, rs 17535213, rs 10072056, rs 10054825, rs 12546235, rs4242389, rs2071336, rs414634, rsl7725712, rsl 1773821, rs8005905, and rs9482888. In one embodiment, at least one detected SNP is rsl2368829. In another embodiment, at least one detected SNP is rs4147385. In another embodiment, at least one detected SNP is rsl 1744216. In another embodiment, at least one detected SNP is rsl863993. In another embodiment, at least one

WO 2011/131774

PCT/EP2011/056471 detected SNP is rsl7535213. In another embodiment, at least one detected SNP is rsl0072056. In another embodiment, at least one detected SNP is rsi0054825. In another embodiment, at ^H least one detected SNP is rs 12546235. In another embodiment, at least one detected SNP is rs4242389. In another embodiment, at least one detected SNP is rs2071336. In another embodiment, at least one detected SNP is rs414634. In another embodiment, at least one detected SNP is rsl7725712. In another embodiment, at least one detected SNP is rsi 1773821. In another embodiment, at least one detected SNP is rs8005905. In another embodiment, at least one detected SNP is rs9482888.

a) Prior to Factor VIII Therapy [0124] In one embodiment, the present invention relates specifically to an individual or group of individuals diagnosed with severe Hemophilia A that have not previously received Factor VIII therapy (i.e., not received treatment comprising administration of Factor VIII).

[0125] In one embodiment, a method is provided for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with severe Hemophilia A, who 5 has not previously received treatment comprising administration of FVIII, comprising detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4, in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII.

[0126] In one embodiment of the method, the individual has been diagnosed with mild

Hemophilia. In another embodiment, the individual has been diagnosed with moderate Hemophilia. In yet another embodiment, the individual has been diagnosed with severe Hemophilia.

[0127] In one embodiment of the method, the step of detecting the presence of at least one SNP comprises amplifying a nucleic acid present in the biological sample. In another embodiment, the step of detecting the presence of at least one SNP comprises a technique selected from the group consisting of mass spectroscopy, RT-PCR, microarray hybridization, pyrosequencing, thermal cycle sequencing, capillary array sequencing, solid phase sequencing, a hybridization-based method, an enzymatic-based method, a PCR-based method, a sequencing method, a ssDNA conformational method, and a DNA melting temperature assay.

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 [0128] In one embodiment, the method further comprises assigning and/or administering a treatment to the individual based on the predicted risk of developing antibodies against Factor VIII. In a specific embodiment, treatment comprising administration of Factor VIII is assigned to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In 5 another specific embodiment, treatment comprising Factor VIII bypass therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0129] In yet another specific embodiment, combination therapy comprising administration of Factor VIII and a FVIII bypass agent is assigned to an individual based on the predicted risk of developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is 0 assigned to an individual with a predicted decreased risk of developing antibodies against Factor

VIII. In another specific embodiment, a combination therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0130] In one embodiment, treatment comprising administration of Factor VIII is provided to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In 5 another specific embodiment, treatment comprising Factor VIII bypass therapy is provided to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0131] In yet another embodiment, combination therapy comprising administration of Factor VIII and a FVIII bypass agent is provided to an individual based on the predicted risk of developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is 0 provided to an individual with a predicted decreased risk of developing antibodies against Factor

VIII. In another specific embodiment, a combination therapy is provided to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0132] In one embodiment, the method further comprises adjusting a dosage of a treatment comprising administration of Factor VIII to the individual based on the predicted risk of developing antibodies against Factor VIII. In a specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII is increased. In another specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted increased risk of developing antibodies against Factor VIII is decreased.

[0133] In another embodiment, the method further comprises adjusting the dosage and/or frequency of Factor VIII administration in a combination therapy based on the predicted risk of

WO 2011/131774

PCT/EP2011/056471 developing antibodies against FVIII. In one embodiment, the method comprises increasing the dosage or frequency of Factor VIII administered in a combination therapy to an individual with a ^H predicted decreased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or frequency of Factor VIII administered in a combination therapy to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0134] In another embodiment, the method further comprises adjusting the dosage and/or frequency of a non-FVIII hemostatic agent administered in a combination therapy based on the predicted risk of developing antibodies against FVIII. In one embodiment, the method comprises increasing the dosage or frequency of a non-FVIII hemostatic agent administered in a combination therapy to an individual with a predicted increased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or frequency of a non-FVIII hemostatic agent administered in a combination therapy to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0135] In another embodiment, the method further comprises adjusting the dosage and/or frequency of both Factor VIII and a non-FVIII hemostatic agent administered in a combination therapy based on the predicted risk of developing antibodies against FVIII. In this fashion, a combination therapy may be optimized for an individual with a specific predicted risk of developing antibodies against FVIII. Optimization of the dosage and/or frequency of Factor VIII and non-FVIII hemostatic agents in combination therapy may be achieved by any combination of increasing the frequency of FVIII administration, decreasing the frequency of FVIII administration, increasing the dosage of FVIII, decreasing the dosage of FVIII, increasing the frequency of non-FVIII hemostatic agent administration, decreasing the frequency of non-FVIII hemostatic agent administration, increasing the dosage of a non-FVIII hemostatic agent, and decreasing the dosage of a non-FVIII hemostatic agent.

[0136] In a specific embodiment, the method comprises increasing the frequency and/or dosage of FVIII and decreasing the frequency and/or dosage of a non-FVIII hemostatic agent administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0137] In another specific embodiment, the method comprises decreasing the frequency and/or dosage of FVIII and increasing the frequency and/or dosage of a non-FVIII hemostatic agent

WO 2011/131774

PCT/EP2011/056471 administered to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0138] In a preferred embodiment, the method comprises the detection of at least one SNP selected from those listed in Table 4. In a specific embodiment, the method comprises the detection of at least on SNP selected from the group consisting of rsl2368829, rs4147385, rsl 1744216, rs 1863993, rs 17535213, rs 10072056, rs 10054825, rs 12546235, rs4242389, rs2071336, rs414634, rsl7725712, rsl 1773821, rs8005905, and rs9482888. In one embodiment, at least one detected SNP is rsl2368829. In another embodiment, at least one detected SNP is rs4147385. In another embodiment, at least one detected SNP is rsl 1744216. In another embodiment, at least one detected SNP is rsl863993. In another embodiment, at least one detected SNP is rsl7535213. In another embodiment, at least one detected SNP is rsl0072056. In another embodiment, at least one detected SNP is rsl0054825. In another embodiment, at least one detected SNP is rs 12546235. In another embodiment, at least one detected SNP is rs4242389. In another embodiment, at least one detected SNP is rs2071336. In another embodiment, at least one detected SNP is rs414634. In another embodiment, at least one detected SNP is rsl7725712. In another embodiment, at least one detected SNP is rsl 1773821. In another embodiment, at least one detected SNP is rs8005905. In another embodiment, at least one detected SNP is rs9482888.

b) After Initial Factor VIII Therapy [0139] In one embodiment, the present invention relates specifically to an individual or group of individuals diagnosed with severe Hemophilia A that have previously received Factor VIII therapy (i.e., received treatment comprising administration of Factor VIII).

[0140] In one embodiment, a method is provided for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with severe Hemophilia A, who 25 has previously received treatment comprising administration of FVIII, comprising detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4, in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII.

[0141] In one embodiment of the method, the individual has been diagnosed with mild

Hemophilia. In another embodiment, the individual has been diagnosed with moderate

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

Hemophilia. In yet another embodiment, the individual has been diagnosed with severe Hemophilia.

[0142] In one embodiment of the method, the step of detecting the presence of at least one SNP comprises amplifying a nucleic acid present in the biological sample. In another embodiment, the step of detecting the presence of at least one SNP comprises a technique selected from the group consisting of mass spectroscopy, RT-PCR, microarray hybridization, pyrosequencing, thermal cycle sequencing, capillary array sequencing, solid phase sequencing, a hybridization-based method, an enzymatic-based method, a PCR-based method, a sequencing method, a ssDNA conformational method, and a DNA melting temperature assay.

[0143] In one embodiment, the method further comprises assigning and/or administering a treatment to the individual based on the predicted risk of developing antibodies against Factor VIII. In a specific embodiment, treatment comprising administration of Factor VIII is assigned to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, treatment comprising Factor VIII bypass therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0144] In yet another specific embodiment, combination therapy comprising administration of Factor VIII and a FVIII bypass agent is assigned to an individual based on the predicted risk of developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is assigned to an individual with a predicted decreased risk of developing antibodies against Factor 0 VIII. In another specific embodiment, a combination therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0145] In one embodiment, treatment comprising administration of Factor VIII is provided to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another specific embodiment, treatment comprising Factor VIII bypass therapy is provided to an 25 individual with a predicted increased risk of developing antibodies against Factor VIII.

[0146] In yet another embodiment, combination therapy comprising administration of Factor VIII and a FVIII bypass agent is provided to an individual based on the predicted risk of developing antibodies against Factor VIII. In one specific embodiment, a combination therapy is provided to an individual with a predicted decreased risk of developing antibodies against Factor 30 VIII. In another specific embodiment, a combination therapy is provided to an individual with a predicted increased risk of developing antibodies against Factor VIII.

WO 2011/131774

PCT/EP2011/056471 [0147] In one embodiment, the method further comprises adjusting a dosage of a treatment comprising administration of Factor VIII to the individual based on the predicted risk of ^H developing antibodies against Factor VIII. In a specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted decreased risk of developing antibodies against 5 Factor VIII is increased. In another specific embodiment, a dosage of Factor VIII to be administered to an individual with a predicted increased risk of developing antibodies against Factor VIII is decreased.

[0148] In another embodiment, the method further comprises adjusting the dosage and/or frequency of Factor VIII administration in a combination therapy based on the predicted risk of 0 developing antibodies against FVIII. In one embodiment, the method comprises increasing the dosage or frequency of Factor VIII administered in a combination therapy to an individual with a predicted decreased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or frequency of Factor VIII administered in a combination therapy to an individual with a predicted increased risk of developing antibodies 5 against Factor VIII.

[0149] In another embodiment, the method further comprises adjusting the dosage and/or frequency of a non-FVIII hemostatic agent administered in a combination therapy based on the predicted risk of developing antibodies against FVIII. In one embodiment, the method comprises increasing the dosage or frequency of a non-FVIII hemostatic agent administered in a 0 combination therapy to an individual with a predicted increased risk of developing antibodies against Factor VIII. In another embodiment, the method comprises decreasing the dosage or frequency of a non-FVIII hemostatic agent administered in a combination therapy to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0150] In another embodiment, the method further comprises adjusting the dosage and/or frequency of both Factor VIII and a non-FVIII hemostatic agent administered in a combination therapy based on the predicted risk of developing antibodies against FVIII. In this fashion, a combination therapy may be optimized for an individual with a specific predicted risk of developing antibodies against FVIII. Optimization of the dosage and/or frequency of Factor VIII and non-FVIII hemostatic agents in combination therapy may be achieved by any combination of increasing the frequency of FVIII administration, decreasing the frequency of FVIII administration, increasing the dosage of FVIII, decreasing the dosage of FVIII, increasing the

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 frequency of non-FVIII hemostatic agent administration, decreasing the frequency of non-FVIII hemostatic agent administration, increasing the dosage of a non-FVIII hemostatic agent, and decreasing the dosage of a non-FVIII hemostatic agent.

[0151] In a specific embodiment, the method comprises increasing the frequency and/or dosage of FVIII and decreasing the frequency and/or dosage of a non-FVIII hemostatic agent administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0152] In another specific embodiment, the method comprises decreasing the frequency and/or dosage of FVIII and increasing the frequency and/or dosage of a non-FVIII hemostatic agent administered to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0153] In a preferred embodiment, the method comprises the detection of at least one SNP selected from those listed in Table 4. In a specific embodiment, the method comprises the detection of at least on SNP selected from the group consisting of rsl2368829, rs4147385, rs 11744216, rs 1863993, rs 17535213, rs 10072056, rs 10054825, rs 12546235, rs4242389, rs2071336, rs414634, rsl7725712, rsl 1773821, rs8005905, and rs9482888. In one embodiment, at least one detected SNP is rsl2368829. In another embodiment, at least one detected SNP is rs4147385. In another embodiment, at least one detected SNP is rsl 1744216. In another embodiment, at least one detected SNP is rsl863993. In another embodiment, at least one detected SNP is rsl7535213. In another embodiment, at least one detected SNP is rsl0072056. In another embodiment, at least one detected SNP is rsl0054825. In another embodiment, at least one detected SNP is rs 12546235. In another embodiment, at least one detected SNP is rs4242389. In another embodiment, at least one detected SNP is rs2071336. In another embodiment, at least one detected SNP is rs414634. In another embodiment, at least one detected SNP is rsl7725712. In another embodiment, at least one detected SNP is rsl 1773821. In another embodiment, at least one detected SNP is rs8005905. In another embodiment, at least one detected SNP is rs9482888.

B. Predictive Markers [0154] Among other aspects, the present invention provides novel markers consisting of SNPs for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 diagnosed with Hemophilia A. Any individual SNP provided in Tables 1 to 4 may be used in conjunction with any other individual SNP provided in Tables 1 to 4 in the methods provided herein for the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia A.

[0155] As such, the present invention contemplates methods for detecting the identity of the nucleotide corresponding to the genomic position of any single SNP listed in Tables 1 to 4 in a biological sample from an individual diagnosed with Hemophilia A. In another embodiment, the method comprises detecting the identity of the nucleotide corresponding to the genomic position of at least 2 SNPs listed in Tables 1 to 4 in a sample from an individual diagnosed with

Hemophilia A. In yet other embodiments, methods are provided for detecting the identity of the nucleotide corresponding to the genomic position of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,

15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,

41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66,

67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92,

93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113,

114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131,132,

133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150,151,

152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169,170,

171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187, 188,189,

190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207,208,

209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, more, or all of the SNPs listed in

Tables 1 to 4.

[0156] In a related embodiment, the present invention contemplates methods for detecting the presence of any SNP listed in Tables 1 to 4 in a biological sample from an individual diagnosed 25 with Hemophilia A. In another embodiment, the method comprises detecting the presence of at least 2 SNPs listed in Tables 1 to 4 in a sample from an individual diagnosed with Hemophilia A. In yet other embodiments, methods are provided for detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33,

34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59,

60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85,

86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108,

109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127,

WO 2011/131774

PCT/EP2011/056471

128, 129, 130, 131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146,

147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, ^H 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184,

185, 186, 187, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203,

204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, more, or all of the SNPs listed in Tables 1 to 4. Generally, detecting the presence of at least one SNP in a biological sample from an individual diagnosed with Hemophilia A may comprise detecting the identity of the nucleotide corresponding to the genomic position of multiple SNPs listed in Tables 1 to 4.

[0157] In certain embodiments, these SNPs may be used in conjunction with other markers known in the art as useful to help predict the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia A. Non-limiting examples of other markers include, various epitopes and allelic variations of the Factor VIII gene and gene product (see, Millar DS et al., Hum Genet. 1990 Dec;86(2):219-27; Kazazian HH Jr et al., Nature 1988 Mar

10;332(6160): 164-6; and Ostertag EM et al., Annu Rev Genet. 2001;35:501-38, the disclosures of which are hereby incorporated by reference in their entireties for all purposes).

[0158] Genomic information regarding the SNPs listed in Tables 1 to 4 can be obtained from the ENTREZ SNP database accessible via the website for the National Center for Biotechnology Information (NCBI). For example, as can be found on the server mentioned above, SNP rs 12368829 corresponds to an A/G single nucleotide polymorphism (SNP) at position

94,473,201 of human chromosome 12 according to build 37.1 of the Celera whole genome sequence. The sequence flanking the SNP comprises the following sequence, with the SNP position underlined in brackets: TTGCCACTACTTGTCTCCAAAGAAACJA/G1TAAGAATGCTTTATCATACAACAGT (SEQ ID NO:1). Based on the sequence information provided by the NCBI server, one of skill in the art will readily be able to determine the identity of the nucleotide at a position corresponding to any one of the SNPs listed in Tables 1 to 4 in a biological sample from an individual diagnosed with Hemophilia A. Accordingly, Applicants hereby incorporate the information provided on the NCBI server for each of the SNPs listed in Tables 1 to 4 into the present application in its entirety for all purposes.

WO 2011/131774

PCT/EP2011/056471 [0159] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 1003854. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl003854 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1003854 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0160] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10054825. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsi0054825 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10054825 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0161] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10072056. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 10072056 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10072056 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0162] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1007212. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl007212 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1007212 is predictive of an increased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0163] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10074391. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl0074391 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10074391 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0164] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 1007822. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl007822 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1007822 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0165] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10104302. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 10104302 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10104302 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0166] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl0165797. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl0165797 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl0165797 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0167] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl0261447. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl0261447 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs!0261447 is predictive of a decreased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0168] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10406354. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsi0406354 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10406354 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0169] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rsl041067. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl041067 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1041067 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0170] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1044141. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl044141 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1044141 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0171] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1046780. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1046780 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1046780 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0172] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10497208. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl0497208 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10497208 is predictive of a decreased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0173] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1050382. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl050382 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1050382 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0174] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 10514071. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl0514071 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10514071 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0175] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1058240. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1058240 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1058240 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0176] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl062069. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1062069 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1062069 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0177] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1075846. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl075846 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1075846 is predictive of a decreased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0178] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10772120. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl0772120 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10772120 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0179] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 10789841. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl0789841 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10789841 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0180] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10797666. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl0797666 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10797666 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0181] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10807350. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 10807350 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10807350 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0182] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10836342. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl0836342 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10836342 is predictive of an increased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0183] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10854166. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsi0854166 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10854166 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0184] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 10972149. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl0972149 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10972149 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0185] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 10977434. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl0977434 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 10977434 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0186] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl 1015985. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl 1015985 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl 1015985 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0187] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl 1032349. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl 1032349 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl 1032349 is predictive of a decreased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0188] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsi 105238. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsi 105238 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsi 105238 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0189] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rsl 1168267. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl 1168267 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl 1168267 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0190] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl 1214108. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl 1214108 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl 1214108 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0191] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 11237451. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsi 1237451 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 11237451 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0192] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsi 1265416. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsi 1265416 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsi 1265416 is predictive of an increased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0193] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1131510. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1131510 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1131510 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0194] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rsl 1574113. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl 1574113 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl 1574113 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0195] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl 1740298. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl 1740298 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl 1740298 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0196] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsi 1744216. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsi 1744216 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsi 1744216 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0197] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsi 1773821. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsi 1773821 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsi 1773821 is predictive of a decreased risk of developing

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0198] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsi 1780679. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsi 1780679 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsi 1780679 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0199] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rsl 1833550. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl 1833550 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl 1833550 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0200] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl 1852361. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl 1852361 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl 1852361 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0201] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl 1952962. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl 1952962 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl 1952962 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0202] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl2001295. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 12001295 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12001295 is predictive of an increased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0203] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12034383. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 12034383 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12034383 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0204] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 12039194. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl2039194 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12039194 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0205] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12051769. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl2051769 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12051769 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0206] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1206486. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1206486 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1206486 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0207] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl2185980. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl2185980 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl2185980 is predictive of an increased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0208] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12310405. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl2310405 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12310405 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0209] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 12325842. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl2325842 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12325842 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0210] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12368829. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 12368829 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12368829 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0211] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12451415. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 12451415 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12451415 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0212] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12506181. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl2506181 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12506181 is predictive of a decreased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0213] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12546235. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 12546235 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12546235 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0214] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 12546235. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 12546235 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12546235 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0215] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12625871. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl2625871 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12625871 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0216] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1264456. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1264456 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1264456 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0217] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12667537. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl2667537 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12667537 is predictive of a decreased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0218] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1267843. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1267843 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1267843 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0219] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 12692566. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 12692566 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12692566 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0220] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12810163. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl2810163 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl2810163 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0221] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12814009. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 12814009 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12814009 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0222] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl2831813. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl2831813 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs!2831813 is predictive of a decreased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0223] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 12881815. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 12881815 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12881815 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0224] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 12959952. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 12959952 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 12959952 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0225] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl2969613. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl2969613 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl2969613 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0226] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 13042473. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 13042473 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 13042473 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0227] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 13096099. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl3096099 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 13096099 is predictive of a decreased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0228] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 13172280. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl3172280 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 13172280 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0229] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 13173943. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl3173943 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 13173943 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0230] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 13206518. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl3206518 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsi3206518 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0231] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1378796. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1378796 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1378796 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0232] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl411479. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl411479 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl411479 is predictive of an increased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0233] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1436522. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1436522 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1436522 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0234] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 1457238. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1457238 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1457238 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0235] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1465073. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1465073 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1465073 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0236] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1519602. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1519602 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1519602 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0237] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1523474. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl523474 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1523474 is predictive of a decreased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0238] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1552323. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl552323 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1552323 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0239] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 1567748. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl567748 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1567748 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0240] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1573706. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl573706 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1573706 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0241] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 161021. In one embodiment, a method is provided for predicting the risk of 0 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 161021 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 161021 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising 5 administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be 0 administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs 25 listed in Tables 1, 2, 3, and 4.

[0242] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 161042. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising 30 the steps of detecting the presence SNP rs 161042 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 161042 is predictive of a decreased risk of developing antibodies against

WO 2011/131774

PCT/EP2011/056471

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further ^H comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0243] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1638006. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl638006 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1638006 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0244] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 169142. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 169142 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl69142 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0245] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17110948. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl7110948 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17110948 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0246] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17113227. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 17113227 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17113227 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0247] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17141840. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl7141840 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl7141840 is predictive of an increased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0248] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl7201075. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl7201075 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl7201075 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0249] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 17228097. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 17228097 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17228097 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0250] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1724120. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl724120 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1724120 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0251] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17283264. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 17283264 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17283264 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0252] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17317153. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl7317153 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17317153 is predictive of an increased risk of developing

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0253] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17419586. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl7419586 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17419586 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

WO 2011/131774

PCT/EP2011/056471 [0254] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 17535213. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl7535213 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17535213 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0255] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17652304. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl7652304 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17652304 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0256] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17671456. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 17671456 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17671456 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0257] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17725712. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 17725712 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17725712 is predictive of an increased risk of developing

100

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0258] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17748322. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 17748322 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17748322 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

101

WO 2011/131774

PCT/EP2011/056471 [0259] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 17763453. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl7763453 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17763453 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0260] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17811425. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 17811425 in a biological sample from the 25 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17811425 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

102

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0261] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17815972. In one embodiment, a method is provided for predicting the risk 0 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 17815972 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17815972 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0262] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1781795. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1781795 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1781795 is predictive of an increased risk of developing

103

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0263] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 17834679. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 17834679 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17834679 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

104

WO 2011/131774

PCT/EP2011/056471 [0264] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 17875513. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl7875513 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 17875513 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0265] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1797646. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl797646 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1797646 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

105

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0266] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1797647. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1797647 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1797647 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0267] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl838065. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl838065 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl838065 is predictive of an increased risk of developing

106

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0268] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl863993. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl863993 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl863993 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

107

WO 2011/131774

PCT/EP2011/056471 [0269] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rsi865462. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsi865462 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsi865462 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0270] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl877563. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl877563 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl877563 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

108

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0271] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsi882019. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl882019 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl882019 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0272] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsi884564. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsi884564 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsi884564 is predictive of a decreased risk of developing

109

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0273] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rsl885831. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl885831 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rsl885831 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

110

WO 2011/131774

PCT/EP2011/056471 [0274] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs 1892803. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1892803 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1892803 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0275] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1918309. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1918309 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1918309 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

111

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0276] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1983165. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs 1983165 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1983165 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0277] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs 1984399. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rsl984399 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs 1984399 is predictive of an increased risk of developing

112

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0278] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2010452. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2010452 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2010452 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

113

WO 2011/131774

PCT/EP2011/056471 [0279] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs2020902. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2020902 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2020902 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0280] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2069933. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2069933 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2069933 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

114

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0281] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2070123. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2070123 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2070123 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0282] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2070783. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2070783 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2070783 is predictive of an increased risk of developing

115

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0283] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2071081. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2071081 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2071081 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

116

WO 2011/131774

PCT/EP2011/056471 [0284] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs2071336. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2071336 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2071336 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0285] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2076620. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2076620 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2076620 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

117

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0286] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2076846. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2076846 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2076846 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group 25 consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0287] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs208250. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising 30 the steps of detecting the presence SNP rs208250 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs208250 is predictive of an increased risk of developing antibodies against

118

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0288] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs210431. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs210431 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs210431 is predictive of an increased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method 25 further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 30 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

119

WO 2011/131774

PCT/EP2011/056471 [0289] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs2157605. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2157605 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2157605 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0290] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2163057. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2163057 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2163057 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

120

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0291] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2179694. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2179694 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2179694 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0292] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2227562. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2227562 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2227562 is predictive of a decreased risk of developing

121

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0293] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2227827. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2227827 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2227827 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

122

WO 2011/131774

PCT/EP2011/056471 [0294] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs2231375. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2231375 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2231375 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0295] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2238337. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2238337 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2238337 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

123

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0296] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2242660. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2242660 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2242660 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0297] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2255364. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2255364 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2255364 is predictive of an increased risk of developing

124

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0298] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2267908. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2267908 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2267908 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

125

WO 2011/131774

PCT/EP2011/056471 [0299] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs2268890. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2268890 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2268890 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0300] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2275603. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2275603 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2275603 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

126

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0301] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2278324. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2278324 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2278324 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0302] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2279590. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2279590 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2279590 is predictive of an increased risk of developing

127

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0303] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2283539. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2283539 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2283539 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

128

WO 2011/131774

PCT/EP2011/056471 [0304] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs2286414. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2286414 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2286414 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0305] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2287768. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2287768 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2287768 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

129

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0306] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2288522. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2288522 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2288522 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0307] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2295616. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2295616 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2295616 is predictive of a decreased risk of developing

130

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0308] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2296449. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2296449 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2296449 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

131

WO 2011/131774

PCT/EP2011/056471 [0309] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs2298877. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2298877 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2298877 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0310] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2302267. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2302267 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2302267 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

132

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0311] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2302759. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2302759 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2302759 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0312] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2302821. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2302821 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2302821 is predictive of a decreased risk of developing

133

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0313] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2305340. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2305340 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2305340 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

134

WO 2011/131774

PCT/EP2011/056471 [0314] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs2335478. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2335478 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2335478 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0315] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs241430. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs241430 in a biological sample from the individual; and 25 predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs241430 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be

135

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 5 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0316] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs244076. In one embodiment, a method is provided for predicting the risk of 0 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs244076 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs244076 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising 5 administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be 0 administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0317] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs244090. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising 30 the steps of detecting the presence SNP rs244090 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs244090 is predictive of an increased risk of developing antibodies against

136

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0318] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs244091. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs244091 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs244091 is predictive of an increased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method 25 further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 30 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

137

WO 2011/131774

PCT/EP2011/056471 [0319] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs244656. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs244656 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs244656 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0320] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs246390. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs246390 in a biological sample from the individual; and 25 predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs246390 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be

138

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0321] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs246392. In one embodiment, a method is provided for predicting the risk of 0 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs246392 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs246392 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0322] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs246394. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising 30 the steps of detecting the presence SNP rs246394 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs246394 is predictive of a decreased risk of developing antibodies against

139

WO 2011/131774

PCT/EP2011/056471

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further ^H comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0323] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs246395. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs246395 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs246395 is predictive of a decreased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

140

WO 2011/131774

PCT/EP2011/056471 [0324] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs2569190. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2569190 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2569190 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0325] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2575674. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2575674 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2575674 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

141

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0326] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2584019. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2584019 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2584019 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0327] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2595204. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2595204 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2595204 is predictive of an increased risk of developing

142

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0328] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2596606. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2596606 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2596606 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

143

WO 2011/131774

PCT/EP2011/056471 [0329] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs2838733. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2838733 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2838733 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0330] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2844463. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2844463 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2844463 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

144

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0331] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2853884. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2853884 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2853884 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0332] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2869460. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2869460 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2869460 is predictive of a decreased risk of developing

145

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0333] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs2869461. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2869461 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2869461 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

146

WO 2011/131774

PCT/EP2011/056471 [0334] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs2879097. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs2879097 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs2879097 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0335] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3024486. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3024486 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3024486 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

147

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0336] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3024498. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3024498 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3024498 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group 25 consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0337] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs304839. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising 30 the steps of detecting the presence SNP rs304839 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs304839 is predictive of an increased risk of developing antibodies against

148

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0338] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs310247. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs310247 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs310247 is predictive of an increased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method 25 further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 30 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

149

WO 2011/131774

PCT/EP2011/056471 [0339] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs31519. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs31519 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs31519 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0340] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3181096. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3181096 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3181096 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

150

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0341] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3211821. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3211821 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3211821 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0342] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3211834. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3211834 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3211834 is predictive of a decreased risk of developing

151

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0343] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3733236. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3733236 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3733236 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

152

WO 2011/131774

PCT/EP2011/056471 [0344] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs3733678. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3733678 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3733678 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0345] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3736101. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3736101 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3736101 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

153

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0346] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3736395. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3736395 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3736395 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0347] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3788151. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3788151 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3788151 is predictive of a decreased risk of developing

154

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0348] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3795326. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3795326 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3795326 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

155

WO 2011/131774

PCT/EP2011/056471 [0349] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs3797390. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3797390 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3797390 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0350] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3815003. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3815003 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3815003 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

156

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0351] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3816724. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3816724 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3816724 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0352] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3819496. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3819496 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3819496 is predictive of a decreased risk of developing

157

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0353] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3826392. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3826392 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3826392 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

158

WO 2011/131774

PCT/EP2011/056471 [0354] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs3828016. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3828016 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3828016 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0355] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs3845422. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs3845422 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs3845422 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

159

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0356] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs390406. In one embodiment, a method is provided for predicting the risk of 0 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs390406 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs390406 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising 5 administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be 0 administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs 25 listed in Tables 1, 2, 3, and 4.

[0357] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4027402. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4027402 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4027402 is predictive of a decreased risk of developing

160

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0358] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4077341. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4077341 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4077341 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

161

WO 2011/131774

PCT/EP2011/056471 [0359] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs4094864. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4094864 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4094864 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0360] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4104. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4104 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4104 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be

162

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 5 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0361] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs414634. In one embodiment, a method is provided for predicting the risk of 0 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs414634 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs414634 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising 5 administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be 0 administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0362] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4147385. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4147385 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4147385 is predictive of an increased risk of developing

163

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0363] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs424051. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs424051 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs424051 is predictive of a decreased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method 25 further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 30 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

164

WO 2011/131774

PCT/EP2011/056471 [0364] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs4242389. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4242389 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4242389 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0365] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4245886. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4245886 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4245886 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

165

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0366] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4251520. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4251520 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4251520 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0367] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4253655. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4253655 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4253655 is predictive of an increased risk of developing

166

WO 2011/131774

PCT/EP2011/056471 antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the ^H method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0368] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs440238. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs440238 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs440238 is predictive of a decreased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method 25 further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 30 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

167

WO 2011/131774

PCT/EP2011/056471 [0369] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A ^H consisting of SNP rs4462251. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4462251 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4462251 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0370] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4472605. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4472605 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4472605 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising

168

WO 2011/131774

PCT/EP2011/056471 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group ^H consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0371] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4485556. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4485556 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4485556 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0372] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4498385. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4498385 in a biological sample from the

169

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4498385 is predictive of an increased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0373] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4572808. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4572808 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4572808 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

170

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0374] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4639174. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4639174 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4639174 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0375] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4646077. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4646077 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4646077 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

171

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0376] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4698806. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4698806 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4698806 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further 25 comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0377] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4724231. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4724231 in a biological sample from the

172

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4724231 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0378] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4752894. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4752894 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4752894 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

173

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0379] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4752896. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4752896 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4752896 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0380] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4752904. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4752904 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4752904 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

174

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0381] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4756331. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4756331 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4756331 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further 25 comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0382] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4798598. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4798598 in a biological sample from the

175

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4798598 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0383] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4820059. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4820059 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4820059 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

176

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0384] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4902264. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4902264 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4902264 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0385] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4953292. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4953292 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4953292 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

177

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0386] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4955104. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4955104 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4955104 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further 25 comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0387] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4955272. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4955272 in a biological sample from the

178

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4955272 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0388] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs4966019. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs4966019 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs4966019 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

179

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0389] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs496888. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs496888 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs496888 is predictive of a decreased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0390] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs499205. In one embodiment, a method is provided for predicting the risk of 25 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs499205 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs499205 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising

180

WO 2011/131774

PCT/EP2011/056471 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be ^H administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0391] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs509749. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs509749 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs509749 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0392] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs5743220. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs5743220 in a biological sample from the

181

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs5743220 is predictive of an increased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0393] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs5743740. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs5743740 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs5743740 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

182

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0394] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs5746154. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs5746154 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs5746154 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0395] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs599563. In one embodiment, a method is provided for predicting the risk of 25 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs599563 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs599563 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising 30 administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising

183

WO 2011/131774

PCT/EP2011/056471 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be ^H administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0396] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs5996577. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs5996577 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs5996577 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0397] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6016685. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6016685 in a biological sample from the

184

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6016685 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0398] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6021183. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6021183 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6021183 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

185

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0399] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6058391. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6058391 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6058391 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0400] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6060855. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6060855 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6060855 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

186

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0401] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6065460. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6065460 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6065460 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further 25 comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0402] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6065467. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6065467 in a biological sample from the

187

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6065467 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0403] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6093584. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6093584 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6093584 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

188

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0404] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs613613. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs613613 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs613613 is predictive of a decreased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0405] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6214. In one embodiment, a method is provided for predicting the risk of 25 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6214 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6214 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising

189

WO 2011/131774

PCT/EP2011/056471 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be ^H administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0406] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs638251. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs638251 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs638251 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0407] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6476985. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6476985 in a biological sample from the

190

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6476985 is predictive of an increased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0408] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6482644. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6482644 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6482644 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

191

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0409] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6482647. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6482647 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6482647 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0410] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6544865. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6544865 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6544865 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

192

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0411] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6580942. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6580942 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6580942 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further 25 comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0412] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs660597. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs660597 in a biological sample from the individual; and

193

WO 2011/131774

PCT/EP2011/056471 predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs660597 is predictive of a decreased risk of developing antibodies against ^H Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0413] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6621980. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6621980 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6621980 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

194

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0414] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6670616. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6670616 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6670616 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0415] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6742576. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6742576 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6742576 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

195

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0416] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6751395. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6751395 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6751395 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further 25 comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0417] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6769530. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6769530 in a biological sample from the

196

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6769530 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0418] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6780432. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6780432 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6780432 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

197

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0419] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6782288. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6782288 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6782288 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0420] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6829390. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6829390 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6829390 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

198

WO 2011/131774

PCT/EP2011/056471 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising ^H administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0421] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6837303. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6837303 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6837303 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0422] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6850557. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6850557 in a biological sample from the

199

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6850557 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0423] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6863088. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6863088 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6863088 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

200

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0424] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs6917187. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs6917187 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs6917187 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0425] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs704697. In one embodiment, a method is provided for predicting the risk of 25 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs704697 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs704697 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising 30 administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising

201

WO 2011/131774

PCT/EP2011/056471 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be ^H administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0426] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs704853. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs704853 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs704853 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0427] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs706121. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs706121 in a biological sample from the individual; and

202

WO 2011/131774

PCT/EP2011/056471 predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs706121 is predictive of an increased risk of developing antibodies against ^H Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0428] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7072398. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7072398 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7072398 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

203

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0429] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7099752. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7099752 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7099752 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0430] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7124275. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7124275 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7124275 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

204

WO 2011/131774

PCT/EP2011/056471 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising ^H administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0431] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7130876. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7130876 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7130876 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0432] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7170919. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7170919 in a biological sample from the

205

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7170919 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0433] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs717176. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs717176 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs717176 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

206

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0434] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7246376. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7246376 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7246376 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0435] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs728373. In one embodiment, a method is provided for predicting the risk of 25 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs728373 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs728373 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising 30 administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising

207

WO 2011/131774

PCT/EP2011/056471 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be ^H administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0436] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7289754. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7289754 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7289754 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0437] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7290696. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7290696 in a biological sample from the

208

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7290696 is predictive of an increased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0438] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs731305. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs731305 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs731305 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

209

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0439] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7348444. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7348444 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7348444 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0440] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7359387. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7359387 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7359387 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

210

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0441] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7541717. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7541717 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7541717 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further 25 comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0442] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7559522. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7559522 in a biological sample from the

211

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7559522 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0443] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs763361. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs763361 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs763361 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

212

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0444] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7641625. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7641625 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7641625 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0445] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7647903. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7647903 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7647903 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

213

WO 2011/131774

PCT/EP2011/056471 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising ^H administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0446] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs766502. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs766502 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs766502 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0447] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7690305. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7690305 in a biological sample from the

214

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7690305 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0448] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7692976. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7692976 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7692976 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

215

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0449] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP 146106438. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP 146106438 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP 146106438 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0450] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7732671. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7732671 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7732671 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

216

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0451] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7851161. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7851161 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7851161 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further 25 comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0452] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs791587. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs791587 in a biological sample from the individual; and

217

WO 2011/131774

PCT/EP2011/056471 predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs791587 is predictive of a decreased risk of developing antibodies against ^H Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0453] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs793816. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs793816 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs793816 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

218

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0454] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs7987909. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs7987909 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs7987909 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0455] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs8005905. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs8005905 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs8005905 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

219

WO 2011/131774

PCT/EP2011/056471 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising ^H administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0456] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs805274. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs805274 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs805274 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0457] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs805287. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs805287 in a biological sample from the individual; and

220

WO 2011/131774

PCT/EP2011/056471 predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs805287 is predictive of a decreased risk of developing antibodies against ^H Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0458] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs8064821. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs8064821 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs8064821 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

221

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0459] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs8078439. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs8078439 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs8078439 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0460] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs8086815. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs8086815 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs8086815 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

222

WO 2011/131774

PCT/EP2011/056471 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising ^H administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0461] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs831603. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs831603 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs831603 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0462] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs832517. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs832517 in a biological sample from the individual; and

223

WO 2011/131774

PCT/EP2011/056471 predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs832517 is predictive of a decreased risk of developing antibodies against ^H Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0463] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs866484. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs866484 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs866484 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

224

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0464] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs872071. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs872071 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs872071 is predictive of a decreased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0465] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs875258. In one embodiment, a method is provided for predicting the risk of 25 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs875258 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs875258 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising

225

WO 2011/131774

PCT/EP2011/056471 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be ^H administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0466] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs878081. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs878081 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs878081 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0467] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs896769. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs896769 in a biological sample from the individual; and

226

WO 2011/131774

PCT/EP2011/056471 predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs896769 is predictive of a decreased risk of developing antibodies against ^H Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0468] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs910682. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs910682 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs910682 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

227

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0469] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs926479. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs926479 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs926479 is predictive of an increased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0470] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs927010. In one embodiment, a method is provided for predicting the risk of 25 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs927010 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs927010 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising

228

WO 2011/131774

PCT/EP2011/056471 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be ^H administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0471] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs927335. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs927335 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs927335 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0472] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9310940. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9310940 in a biological sample from the

229

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9310940 is predictive of an increased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0473] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9313487. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9313487 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9313487 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

230

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0474] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs933226. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs933226 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs933226 is predictive of an increased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0475] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9426315. In one embodiment, a method is provided for predicting the risk 25 of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9426315 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9426315 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a 30 therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

231

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0476] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9482888. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9482888 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9482888 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further 25 comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0477] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9487735. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9487735 in a biological sample from the

232

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9487735 is predictive of an increased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0478] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs949664. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs949664 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs949664 is predictive of a decreased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

233

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0479] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs970283. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs970283 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs970283 is predictive of a decreased risk of developing antibodies against

Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70,

80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0480] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs976881. In one embodiment, a method is provided for predicting the risk of 25 developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs976881 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs976881 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising

234

WO 2011/131774

PCT/EP2011/056471 administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be ^H administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in

Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0481] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9817149. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9817149 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9817149 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0482] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9826296. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9826296 in a biological sample from the

235

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9826296 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0483] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9831803. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9831803 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9831803 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

236

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0484] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9862163. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9862163 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9862163 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0485] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9867325. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9867325 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9867325 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a

237

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0486] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9892152. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9892152 in a biological sample from the individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9892152 is predictive of an increased risk of developing antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further 25 comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18,

19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

[0487] In one embodiment, the present invention provides a marker useful for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A consisting of SNP rs9991904. In one embodiment, a method is provided for predicting the risk of developing antibodies against FVIII in an individual diagnosed with Hemophilia A comprising the steps of detecting the presence SNP rs9991904 in a biological sample from the

238

WO 2011/131774

PCT/EP2011/056471 individual; and predicting the risk of the individual of developing antibodies to FVIII. In one embodiment, the presence of SNP rs9991904 is predictive of a decreased risk of developing ^H antibodies against Factor VIII. In one embodiment, the method further comprises assigning a therapy comprising administration of Factor VIII to the individual. In another embodiment, the method further comprises assigning a therapy comprising Factor VIII bypass therapy to the individual. In another embodiment, the method further comprises increasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises decreasing a dosage of a therapy comprising administration of FVIII to be administered to the individual. In another embodiment, the method further comprises detecting the presence of at least a second SNP selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4. In another embodiment, the method further comprises detecting the presence of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 30, 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200, or more SNPs selected from the group consisting of the SNPs listed in Tables 1, 2, 3, and 4.

C. Methods for Detecting SNPs [0488] The present invention relies on routine techniques in the field of recombinant genetics. Basic texts disclosing the general methods of use in this invention include Sambrook et al., Molecular Cloning, A Laboratory Manual (3rd ed. 2001); Kriegler, Gene Transfer and Expression: A Laboratory Manual (1990); and Current Protocols in Molecular Biology (Ausubel et al., eds., 1994)). Oligonucleotides that are not commercially available can be chemically synthesized according to the solid phase phosphoramidite triester method first described by Beaucage & Caruthers, Tetrahedron Letts. 22:1859-1862 (1981), using an automated synthesizer, as described in Van Devanter et. al., Nucleic Acids Res. 12:6159-6168 (1984). Purification of oligonucleotides is by either native acrylamide gel electrophoresis or by anion-exchange HPLC as described in Pearson & Reanier, J. Chrom. 255:137-149 (1983).

[0489] Any suitable method can be used to detect (i.e. screen for or identify) a SNP, e.g., restriction fragment length polymorphisms and electrophoretic gel analysis or mass spectroscopy, or PCR analysis. Various real-time PCR methods can be used to detect SNPs, including, e.g., Taqman or molecular beacon-based assays (e.g., U.S. Patent Nos. 5,210,015;

5,487,972; Tyagi et al., Nature Biotechnology 14:303 (1996); and PCT WO 95/13399) are useful to monitor for the presence of absence of a SNP. Additional SNP detection methods include,

239

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

e.g., DNA sequencing, sequencing by hybridization, dot blotting, oligonucleotide array (DNA chip or bead chip) hybridization analysis, or are described in, e.g., U.S. Patent No. 6,177,249; Landegren et al., Genome Research, 8:769-776 (1998); Botstein et al., Am J Human Genetics 32:314-331 (1980); Meyers et al., Methods in Enzymology 155:501-527 (1987); Keen et al.,

Trends in Genetics 7:5 (1991); Myers et al., Science 230:1242-1246 (1985); and Kwok et al., Genomics 23:138-144 (1994).

[0490] Analysis of the genotype of an nucleic acid marker can be performed using techniques known in the art including, without limitation, microarrays, polymerase chain reaction (PCR)based analysis, sequence analysis, and electrophoretic analysis. A non-limiting example of a

PCR-based analysis includes a Taqman® allelic discrimination assay available from Applied Biosystems. Non-limiting examples of sequence analysis include Maxam-Gilbert sequencing, Sanger sequencing, capillary array DNA sequencing, thermal cycle sequencing (Sears et al., Biotechniques, 13:626-633 (1992)), solid-phase sequencing (Zimmerman et al., Methods Mol. Cell Biol., 3:39-42 (1992)), sequencing with mass spectrometry such as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS; Fu et al., Nature Biotech., 16:381-384 (1998)), and sequencing by hybridization (Chee et al., Science, 274:610614 (1996); Drmanac et al., Science, 260:1649-1652 (1993); Drmanac et al., Nature Biotech., 16:54-58 (1998)). Non-limiting examples of electrophoretic analysis include slab gel electrophoresis such as agarose or polyacrylamide gel electrophoresis, capillary electrophoresis, and denaturing gradient gel electrophoresis. Other methods for genotyping a subject at a polymorphic site include, e.g., the INVADER® assay from Third Wave Technologies, Inc., restriction fragment length polymorphism (RFEP) analysis, allele-specific oligonucleotide hybridization, a heteroduplex mobility assay, single strand conformational polymorphism (SSCP) analysis, single-nucleotide primer extension (SNUPE) and pyrosequencing.

[0491] A detectable moiety can be used in the assays described herein. A wide variety of detectable moieties can be used, with the choice of label depending on the sensitivity required, ease of conjugation with the antibody, stability requirements, and available instrumentation and disposal provisions. Suitable detectable moieties include, but are not limited to, radionuclides, fluorescent dyes (e.g., fluorescein, fluorescein isothiocyanate (FITC), Oregon Green™, rhodamine, Texas red, tetrarhodimine isothiocynate (TRITC), Cy3, Cy5, etc.), fluorescent markers (e.g., green fluorescent protein (GFP), phycoerythrin, etc.), autoquenched fluorescent compounds that are activated by tumor-associated proteases, enzymes (e.g., luciferase,

240

WO 2011/131774

PCT/EP2011/056471 horseradish peroxidase, alkaline phosphatase, etc.), nanoparticles, biotin, digoxigenin, and the like.

[0492] Probes are typically labeled either directly, as with isotopes, chromophores, lumiphores, chromogens, or indirectly, such as with biotin, to which a streptavidin complex may later bind. Thus, the detectable labels used in the assays of the present invention can be primary labels (where the label comprises an element that is detected directly or that produces a directly detectable element) or secondary labels (where the detected label binds to a primary label, e.g., as is common in immunological labeling). Typically, labeled signal nucleic acids are used to detect hybridization. Complementary nucleic acids or signal nucleic acids may be labeled by any one of several methods typically used to detect the presence of hybridized polynucleotides.

125 35 14

The most common method of detection is the use of autoradiography with Η, I, S, C, or

P-labeled probes or the like.

[0493] Other labels include, e.g., ligands that bind to labeled antibodies, fhiorophores, chemiluminescent agents, enzymes, and antibodies which can serve as specific binding pair members for a labeled ligand. An introduction to labels, labeling procedures and detection of labels is found in Polak and Van Noorden Introduction to Immunocytochemistry, 2nd ed., Springer Verlag, NY (1997); and in Haugland Handbook of Fluorescent Probes and Research Chemicals, a combined handbook and catalogue Published by Molecular Probes, Inc. (1996).

[0494] In general, a detector which monitors a particular probe or probe combination is used to 0 detect the detection reagent label. Typical detectors include spectrophotometers, phototubes and photodiodes, microscopes, scintillation counters, cameras, film and the like, as well as combinations thereof. Examples of suitable detectors are widely available from a variety of commercial sources known to persons of skill in the art. Commonly, an optical image of a substrate comprising bound labeling moieties is digitized for subsequent computer analysis.

[0495] A variety of automated solid-phase assay techniques are also appropriate. For instance, very large scale immobilized polymer arrays (VLSIPS™), available from Affymetrix, Inc. (Santa Clara, CA) can be used to detect changes in expression levels of a plurality of genes involved in the same regulatory pathways simultaneously. See, Tijssen, supra., Fodor et al. (1991) Science, 251: 767- 777; Sheldon et al. (1993) Clinical Chemistry 39(4): 718-719, and Kozal et al. (1996)

Nature Medicine 2(7): 753-759.

241

WO 2011/131774

PCT/EP2011/056471 [0496] The nucleic acids used in this invention can be either positive or negative probes. Positive probes bind to their targets and the presence of duplex formation is evidence of the ^H presence of the target. Negative probes fail to bind to the suspect target and the absence of duplex formation is evidence of the presence of the target. For example, the use of a wild type 5 specific nucleic acid probe or PCR primers may serve as a negative probe in an assay sample where only the nucleotide sequence of interest is present.

[0497] The sensitivity of the hybridization assays may be enhanced through use of a nucleic acid amplification system that multiplies the target nucleic acid being detected. Examples of such systems include the polymerase chain reaction (PCR) system, in particular RT-PCR or real 0 time PCR, and the ligase chain reaction (LCR) system. Other methods recently described in the art are the nucleic acid sequence based amplification (NASBA, Cangene, Mississauga, Ontario) and Q Beta Replicase systems. These systems can be used to directly identify mutants where the PCR or LCR primers are designed to be extended or ligated only when a selected sequence is present. Alternatively, the selected sequences can be generally amplified using, for example, 5 nonspecific PCR primers and the amplified target region later probed for a specific sequence indicative of a mutation.

[0498] In some embodiments of the present invention, the target nucleic acid or the probe is immobilized on a solid support. Solid supports suitable for use in the assays of the invention are known to those of skill in the art. As used herein, a solid support is a matrix of material in a 0 substantially fixed arrangement. One preferred example is the Illumina® BeadChip array. The array comprises silica beads which are self-assembled into ordered microwells. Each 3 pm silica bead comprises a plurality of 50mer, transcript-specific oligonucleotide probes that have been immobilized on the bead. To generate a BeadChip, thousands to tens of thousands of unique oligonucleotides, each complementary to a different target sequence, are synthesized. These oligos are then immobilized in separate reactions to the beads, generating a corresponding number of unique bead types. The beads are pooled together, and then loaded by a self-assembly process into microwells that have been etched into the surface of a BeadChip. Each bead type is represented on the array surface an average of more than thirty times.

[0499] In some embodiments, the identification of a single nucleotide polymorphism of the 30 present invention is accomplished through the use of a whole-genome amplification method.

One preferred example is the Illumina® Infinium® assay. Briefly, 750 ng of human genomic

242

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

DNA is isothermally amplified overnight. The amplified product is then fragmented by a controlled enzymatic digestion. The DNA is then precipitated and resuspended and applied to a BeadChip that has been prepared for hybridization. DNA samples are applied to the BeadChip and incubated overnight. The amplified and fragmented DNA samples anneal to locus-specific

50-mers (on beads). Each bead type corresponds to each allele per SNP locus. After hybridization, allelic specificity is conferred by enzymatic base extension and revealed by fluorescent staining.

IV. Compositions, Kits, and Arrays [0500] The invention also provides compositions, kits, and arrays for practicing the methods 0 described herein using polynucleotides of the invention.

[0501] In some embodiments, the oligonucleotides, kits, and arrays of the present invention may be used to predict the risk of an individual developing antibodies to factor VIII (FVIII) and to adjust a dosage of FVIII therapy received by the individual. In some embodiments, the oligonucleotides, kits, and arrays of the present invention may be used to predict the risk of an individual developing antibodies to FVIII and to adjust a dosage of bypass therapy received by the individual.

A. Probes [0502] In exemplary embodiments, a kit described herein comprises a capture probe or capture probe set. Capture probes sets comprise a plurality of “capture probes,” which are compounds 20 used to detect the presence or absence of, or to quantify, relatively or absolutely, a target species or target sequence. Generally, a capture probe allows the attachment of a target sequence to a solid support for the purposes of detection as further described herein. Attachment of the target species to the capture binding ligand can be direct or indirect and can be covalent or noncovalent. Capture probes that bind directly to a target species may be said to be “selective” 25 for, “specifically bind” or “selectively bind” their target. It should be noted that capture probes are designed to be perfectly or substantially complementary to either of the strands (e.g. either the sense or the antisense strand) of a double stranded polynucleotide, such as a gene. Thus, in some cases, a capture probe described herein is perfectly or substantially complementary to the sense strand; that is, assuming the sense strand is referred to as “Watson”, the capture probe 30 would be “Crick”. In some cases, a capture probe described herein is perfectly or substantially

243

WO 2011/131774

PCT/EP2011/056471 complementary to the antisense strand. For detecting a SNP, a capture probe selective for an allele of a gene typically spans the one or more nucleic acids that differs from corresponding ^H nucleic acids in a different allele of a gene. For detecting an insertion, a capture probe selective for an allele of a gene typically spans one or more nucleic acids that are present compared to the corresponding site in a different allele of a gene in which the nucleic acids are absent. For detecting a deletion, a capture probe selective for an allele of a gene typically spans a site where one or more nucleic acids are absent compared to the corresponding site in a different allele of a gene in which the nucleic acids are present.

[0503] Capture probes that “selectively bind” to or are “selective” for (i.e., are “complementary” or “substantially complementary” to) a target nucleic acid find use in the present invention. “Complementary” or “substantially complementary” refers to the hybridization or base pairing or the formation of a duplex between nucleotides or nucleic acids, such as, for instance, between the two strands of a double stranded DNA molecule or between an oligonucleotide primer and a primer binding site on a single stranded nucleic acid.

Complementary nucleotides are, generally, A and T (or A and U), or C and G. Two single stranded RNA or DNA molecules may be said to be substantially complementary when the nucleotides of one strand, optimally aligned and compared and with appropriate nucleotide insertions or deletions, pair with at least about 80% of the nucleotides of the other strand, usually at least about 90% to 95%, and more preferably from about 98% to 100%, and in some embodiments, at least a percentage selected from 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% and 99%. Where one single stranded RNA or DNA molecule is shorter than another, the two single stranded RNA or DNA molecules may be said to be substantially complementary when the nucleotides of the longer strand, optimally aligned and compared and with appropriate nucleotide insertions or deletions, pair with at least about 80% of the nucleotides of the shorter 25 strand, usually at least about 90% to 95%, and more preferably from about 98% to 100%, and in some embodiments, at least a percentage selected from 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% and 99%. Alternatively, substantial complementarity exists (i.e., one sequence is selective for another) when an RNA or DNA strand will hybridize under selective hybridization conditions (for example, stringent conditions or high stringency conditions as known in the art) 30 to its complement. Typically, selective hybridization will occur when there is at least about 65% complementarity over a stretch of at least 14 to 25 nucleotides, preferably at least about 75%, more preferably at least about 90% (or 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99%)

244

WO 2011/131774

PCT/EP2011/056471 complementarity. (See, M. Kanehisa, Nucleic Acids Res., 2004, 12: 203.) In some embodiments, the term “bind” refers to binding under high stringency conditions. In some ^H embodiments, a capture probe that selectively binds to or is selective for a target is perfectly complementary to the target. In some embodiments, a capture probe that selectively binds to or is selective for a target is substantially complementary to the target.

[0504] “Duplex” means at least two oligonucleotides and/or polynucleotides that are fully or partially complementary undergo Watson-Crick type base pairing among all or most of their nucleotides so that a stable complex is formed. The terms “annealing” and “hybridization” are used interchangeably to mean the formation of a stable duplex. In one embodiment, stable 0 duplex means that a duplex structure is not destroyed by a stringent wash, e.g., conditions including temperature of about 5°C less than the T_m of a strand of the duplex and low monovalent salt concentration, e.g. less than 0.2 M, or less than 0.1 M. “Perfectly matched” in reference to a duplex means that the poly- or oligonucleotide strands making up the duplex form a double stranded structure with one another such that every nucleotide in each strand undergoes 5 Watson-Crick basepairing with a nucleotide in the other strand. The term “duplex” includes the pairing of nucleoside analogs, such as deoxyinosine, nucleosides with 2-aminopurine bases, PNAs, and the like, that may be employed. A “mismatch” in a duplex between two oligonucleotides or polynucleotides means that a pair of nucleotides in the duplex fails to undergo Watson-Crick bonding.

[0505] In exemplary embodiments, each of the probes of a capture probe set is suitable for distinguishing at least two different alleles of a given gene (e.g., a SNP associated with a risk risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia A). The probes or capture probe sets described herein can be used to determine a polymorphism at a gene locus. As understood in the art, an “allele” refers to a particular alternative form of a gene. For convenience, the term “allele” as used herein can also refer to a combination of alleles at multiple loci that are transmitted together on the same chromosome. That is, an allele can refer to a haplotype. An allele can be characterized, for example, by substitution, insertion or deletion of one or more bases relative to a different allele. A capture probe could thus, in various examples, span a polymorphic site of the gene, span one or more insertions or span nucleic acids flanking a deletion.

245

WO 2011/131774

PCT/EP2011/056471 [0506] An allele may be referred to in various ways. For example, an allele may be referred to by a substitution of a nucleotide for another in a parent polynucleotide strand (e.g., genomic ^H DNA, mRNA, fragments thereof, amplification products thereof and other polynucleotides disclosed herein) or by the substitution of an amino acid for another in a parent polypeptide strand (e.g., a polypeptide resulting from translation of a polynucleotide). In some instances, a reference to an amino acid substitution corresponds to a nucleotide variation in the gene that causes that amino acid substitution in the polypeptide resulting from expression of the gene as understood in the art. Where reference is made to a substitution, both a parent molecule (e.g., gene) and a molecule containing the substitution relative to the parent are contemplated and either or both alleles may be probed. Where reference is made to an insertion, both a parent molecule (e.g., gene) and a molecule containing the insertion relative to the parent is contemplated and either or both alleles may be probed. Where reference is made to a deletion, both a parent molecule (e.g., gene) and a molecule containing the deletion relative to the parent is contemplated and either or both alleles may be probed.

[0507] In one embodiment, a capture probe set comprises a probe that is selective for an allele of a gene, (e.g., a gene associated with a SNP listed in any one of Tables 1 to 4). In one embodiment, a capture probe set comprises a pair of probes, one of which is selective for a first allele of a gene and one of which is selective for a second allele of the gene. In some embodiments, a capture probe set comprises a pair of probes, one of which is selective for a wildtype allele of the gene and one of which is selective for a mutant (or “variant”) allele of the gene. The term “wildtype” can in some embodiments refer to a major allele or an allele that is the most frequently occurring allele. The term “variant” can in some embodiments refer to a minor allele or an allele that is not the most frequently occurring allele. In exemplary embodiments, a capture probe set comprises a pair of probes, one of which is selective for a major allele of the gene and one of which is selective for a minor allele of the gene. In some embodiments, a capture probe set comprises more than two probes, each of which is selective for a different allele of the gene. In exemplary embodiments, a capture probe set comprises one or more probes selective for one or more alleles of one or more genes.

[0508] In some embodiments, one or more capture probes are used to identify the base at a detection position. In these embodiments, each different probe comprises a different base at an “interrogation position,” which will differentially hybridize to a base at the detection position of

246

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 the target sequence. By using different probes, each with a different base at the interrogation position, the identification of the base at the detection position is elucidated.

[0509] In one embodiment, all nucleotides outside of the interrogation position in two or more probes are the same as compared between the probes; that is, in some embodiments it is preferable to use probes that have equal all components other than the interrogation position (e.g., both the length of the probes as well as the non-interrogation bases) to allow good discrimination. In some embodiments, it may be desirable to alter other components, in order to maximize discrimination at the detection position. For example, all nucleotides outside of the interrogation position in two probes may be the same except for one or two nucleic acids added to the end of only one probe.

B. Oligonucleotides [0510] The invention provides compositions comprising oligonucleotides for practicing the detection and prediction methods of the invention. The oligonucleotides typically are from 10 to 60 nucleotides in length. In some embodiments, the oligonucleotide is about 45-60 nucleotides in length. Each oligonucleotide is complementary to a target sequence of interest. In some embodiments, the oligonucleotide is complementary to a target sequence of interest that comprises a SNP selected from the group consisting of the SNPs listed in Table 1. In some embodiments, the oligonucleotide is complementary to a target sequence of interest that comprises a SNP located in a gene selected from the group consisting of DOCK2, MAPK9,

F13A1, CD36, and PTPRR. In some embodiments, the oligonucleotide is complementary to a target sequence of interest that comprises a SNP selected from the group consisting of rsl 1744216, rsl3206518, rs3211834, rsl863993, rs4147385, and rsl567748.

C. Diagnostic Kits [0511] The invention also provides kits for carrying out the detection and prediction methods of the invention. The kits comprise at least one or more allele-specific oligonucleotide for the SNP described in Table 1. Diagnostic kits for SNPs generally include means of identifying the SNP, e.g., oligonucleotides suitable for amplifying the SNP and directions for detection. Primers can be 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 50 or more nucleotides in length. The kits may include several oligonucleotide sequences to detect at least one single nucleotide polymorphism (SNP) of the

247

WO 2011/131774

PCT/EP2011/056471 invention, e.g., a first oligonucleotide sequence and/or second and/or third and/or additional oligonucleotides that detect at least one SNP selected from the group consisting of the SNPs ^H listed in Table 1, the SNPs listed in Table 2, the SNPs listed in Table 3, and the SPNs listed in Table 4. Optional additional components of the kit include, for example, positive and negative controls, restriction enzymes, reverse-transcriptase or polymerase, the substrate nucleoside triphosphates, means used to label (for example, an avidinenzyme conjugate and enzyme substrate and chromogen if the label is biotin), and the appropriate buffers for reverse transcription, PCR, or hybridization reactions.

[0512] In some embodiments, the kits may include one or more oligonucleotide sequences to detect at least one SNP selected from the group consisting of rsll744216, rsl3206518, rs3211834, rsl863993, rs4147385, and rsl567748.

[0513] In one embodiment, the present invention provides a diagnostic kit for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the kit comprising at least one oligonucleotide capable of being used to detect at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4. In a preferred embodiment, the at least one SNP is selected from those listed in Table 3. In another preferred embodiment, the at least one SNP is selected from the group consisting of rs 12368829, rsi 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712. In one embodiment, the oligonucleotide capable of being used to detect at least one SNP comprises a sequence complementary to a genomic sequence flanking the SNP. In a specific embodiment, the oligonucleotide sequence that is complementary to the genomic sequence that flanks a SNP includes a nucleotide corresponding to the position of the SNP in the genome. In one embodiment, the nucleotide corresponding to the position of the SNP in the genome is the rare nucleotide (i.e., the SNP). In another embodiment, the nucleotide corresponding to the position of the SNP in the genome is the wild type nucleotide.

[0514] In another embodiment, the present invention provides a diagnostic kit for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with severe Hemophilia, the kit comprising at least one oligonucleotide capable of being used to detect at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4. In a preferred embodiment, the at least one

248

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

SNP is selected from those listed in Table 4. In another preferred embodiment, the at least one SNP is selected from the group consisting of rsl2368829, rs4147385, rsl 1744216, rsl863993, rs 17535213, rs 10072056, rs 10054825, rs 12546235, rs4242389, rs2071336, rs414634, rs 17725712, rsl 1773821, rs8005905, and rs9482888. In one embodiment, the oligonucleotide capable of being used to detect at least one SNP comprises a sequence complementary to a genomic sequence flanking the SNP. In a specific embodiment, the oligonucleotide sequence that is complementary to the genomic sequence that flanks a SNP includes a nucleotide corresponding to the position of the SNP in the genome. In one embodiment, the nucleotide corresponding to the position of the SNP in the genome is the rare nucleotide (/.<?., the SNP). In another embodiment, the nucleotide corresponding to the position of the SNP in the genome is the wild type nucleotide.

D. Oligonucleotide Arrays [0515] The invention also provides assay compositions for use in solid phase assays; such compositions can include, for example, one or more polynucleotides of the invention immobilized on a solid support, and a labeling reagent. In each case, the assay compositions can also include additional reagents that are desirable for hybridization. In preferred embodiments, the solid phase assay is a microarray comprising a support having a plurality of discrete regions, wherein each discrete region comprises one or more nucleic acid fragments spotted thereon. In some embodiments, the one or more nucleic acid fragments spotted on the microarray support comprises a sequence that is complementary to a SNP selected from the group consisting of the SNPs listed in Table 1.

[0516] In one embodiment, the invention provides a microarray for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the microarray comprising a support having a plurality of discrete regions, each discrete region 25 having a nucleic acid fragment spotted thereon, wherein at least one nucleic acid fragment spotted on the support comprises a sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4. In a preferred embodiment, the at least one SNP is selected from those listed in Table 3. In another 30 preferred embodiment, the at least one SNP is selected from the group consisting of rs 12368829, rsl 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213,

249

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 rsl0072056, and rsl7725712. In one embodiment, the oligonucleotide capable of being used to detect at least one SNP comprises a sequence complementary to a genomic sequence flanking the SNP. In a specific embodiment, the oligonucleotide sequence that is complementary to the genomic sequence that flanks a SNP includes a nucleotide corresponding to the position of the

SNP in the genome. In one embodiment, the nucleotide corresponding to the position of the SNP in the genome is the rare nucleotide (i.e., the SNP). In another embodiment, the nucleotide corresponding to the position of the SNP in the genome is the wild type nucleotide.

[0517] In certain embodiments, the microarray comprises at least 2 nucleic acid fragments comprising a sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) listed in Tables 1 to 4, or at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12,

13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,

39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,

65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,

91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,

112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129,130,

131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148,149,

150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167,168,

169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186,187,

188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205,206,

207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, more, or all of the SNPs listed in Tables 1 to 4. In a preferred embodiment, the SNPs are selected from those listed in Tables 1 and 3. In another preferred embodiment, the SNPs are selected from those listed in Table 3.

[0518] In one embodiment, the invention provides a microarray for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the microarray comprising a support having a plurality of discrete regions, each discrete region having a nucleic acid fragment spotted thereon, wherein at least one nucleic acid fragment spotted on the support comprises a sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4. In a preferred embodiment, the at least one SNP is selected from those listed in Table 4. In another preferred embodiment, the at least one SNP is selected from the group consisting of rsl2368829, rs4147385, rsl 1744216, rsl863993,

250

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 rs 17535213, rs 10072056, rs 10054825, rs 12546235, rs4242389, rs2071336, rs414634, rs 17725712, rsi 1773821, rs8005905, and rs9482888. In one embodiment, the oligonucleotide capable of being used to detect at least one SNP comprises a sequence complementary to a genomic sequence flanking the SNP. In a specific embodiment, the oligonucleotide sequence that is complementary to the genomic sequence that flanks a SNP includes a nucleotide corresponding to the position of the SNP in the genome. In one embodiment, the nucleotide corresponding to the position of the SNP in the genome is the rare nucleotide (i.e., the SNP). In another embodiment, the nucleotide corresponding to the position of the SNP in the genome is the wild type nucleotide.

[0519] In certain embodiments, the microarray comprises at least 2 nucleic acid fragments comprising a sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) listed in Tables 2 and 4, or at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,

39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64,

65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90,

91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111,

112, 113, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130,

131, 132, 133, 134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147, 148, 149,

150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168,

169, 170, 171, 172, 173, 174, 175, 176, 177, 178, 179, 180, 181, 182, 183, 184, 185, 186, 187,

188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206,

207, 208, 209, 210, 211, 212, 213, 214, 215, 216, 217, 218, 219, 220, more, or all of the SNPs listed in Tables 1 to 4. In a preferred embodiment, the SNPs are selected from those listed in Table 3.

V. Specific Embodiments [0520] In one embodiment, the present invention provides a method for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the method comprising the steps of: (a) detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed 30 in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4, in a biological sample from the individual; and (b) predicting the risk of the individual of developing antibodies to FVIII.

251

WO 2011/131774

PCT/EP2011/056471 [0521] In one embodiment, the present invention provides a method for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, ^H the method comprising the steps of: (a) detecting the presence of at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4, in a biological sample from the individual; and (b) predicting the risk of the individual of developing antibodies to FVIII, wherein the detection of a SNP associated with an odds ratio of less than 1 is predictive of a decreased risk of developing antibodies against FVIII and the detection of a SNP associated with an odds ratio of more than 1.0 is predictive of an increased risk of developing antibodies against

FVIII.

[0522] In one embodiment of the methods provided above, the individual has not received therapy comprising administration of FVIII.

[0523] In one embodiment of the methods provided above, the individual has received therapy comprising administration of FVIII.

[0524] In one embodiment of the methods provided above, the individual has been diagnosed with mild Hemophilia.

[0525] In one embodiment of the methods provided above, the individual has been diagnosed with moderate Hemophilia.

[0526] In one embodiment of the methods provided above, the individual has been diagnosed with severe Hemophilia.

[0527] In one embodiment of the methods provided above, the at least one single nucleotide polymorphism (SNP) is a SNP listed in Table 2 or a SNP listed in Table 4.

[0528] In one embodiment of the methods provided above, the step of detecting the presence of at least one SNP comprises amplifying a nucleic acid present in the biological sample.

[0529] In one embodiment of the methods provided above, the step of detecting the presence of at least one SNP comprises a technique selected from the group consisting of mass spectroscopy, RT-PCR, microarray hybridization, pyrosequencing, thermal cycle sequencing, capillary array sequencing, and solid phase sequencing.

252

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 [0530] In one embodiment of the methods provided above, the step of detecting the presence of at least one SNP comprises a methods selected from the group consisting of a hybridizationbased method, an enzymatic-based method, a PCR-based method, a sequencing method, a ssDNA conformational method, and a DNA melting temperature assay.

[0531] In one embodiment of the methods provided above, the step of detecting the presence of at least one SNP comprises comprises microarray hybridization.

[0532] In one embodiment of the methods provided above, the SNP is selected from the group consisting of rsl2368829, rsll744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712.

[0533] In one embodiment of the methods provided above, at least one detected SNP is rsl2368829.

[0534] In one embodiment of the methods provided above, at least one detected SNP is rsl 1744216.

[0535] In one embodiment of the methods provided above, at least one detected SNP is rsl863993.

[0536] In one embodiment of the methods provided above, at least one detected SNP is rs4147385.

[0537] In one embodiment of the methods provided above, at least one detected SNP is rs 12546235.

[0538] In one embodiment of the methods provided above, at least one detected SNP is rs4242389.

[0539] In one embodiment of the methods provided above, at least one detected SNP is rs 10054825.

[0540] In one embodiment of the methods provided above, at least one detected SNP is rsl7535213.

[0541] In one embodiment of the methods provided above, at least one detected SNP is rs 10072056.

253

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 [0542] In one embodiment of the methods provided above, at least one detected SNP is rs 17725712.

[0543] In one embodiment of the methods provided above, the SNP is selected from the group consisting of rsl2368829, rs4147385, rsl 1744216, rsl863993, rsl7535213, rsl0072056, rs 10054825, rs 12546235, rs4242389, rs2071336, rs414634, rs 17725712, rsl 1773821, rs8005905, and rs9482888.

[0544] In one embodiment of the methods provided above, at least one detected SNP is rsl2368829.

[0545] In one embodiment of the methods provided above, at least one detected SNP is rs4147385.

[0546] In one embodiment of the methods provided above, at least one detected SNP is rsl 1744216.

[0547] In one embodiment of the methods provided above, at least one detected SNP is rsl863993.

[0548] In one embodiment of the methods provided above, at least one detected SNP is rsl7535213.

[0549] In one embodiment of the methods provided above, at least one detected SNP is rs 10072056.

[0550] In one embodiment of the methods provided above, at least one detected SNP is 20 rsl 0054825.

[0551] In one embodiment of the methods provided above, at least one detected SNP is rs 12546235.

[0552] In one embodiment of the methods provided above, at least one detected SNP is rs4242389.

[0553] In one embodiment of the methods provided above, at least one detected SNP is rs2071336.

[0554] In one embodiment of the methods provided above, at least one detected SNP is rs414634.

254

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 [0555] In one embodiment of the methods provided above, at least one detected SNP is rs 17725712.

[0556] In one embodiment of the methods provided above, at least one detected SNP is rsll773821.

[0557] In one embodiment of the methods provided above, at least one detected SNP is rs8005905.

[0558] In one embodiment of the methods provided above, at least one detected SNP is rs9482888.

[0559] In one embodiment of the methods provided above, the method further comprises 0 assigning a treatment to the individual based on the predicted risk of developing antibodies against Factor VIII.

[0560] In one embodiment of the methods provided above, the treatment comprises administration of Factor VIII.

[0561] In one embodiment of the methods provided above, the treatment comprises administration of a non-Factor VIII hemostatic agent.

[0562] In one embodiment of the methods provided above, the treatment comprises administration of Factor VIII and a non-Factor VIII hemostatic agent.

[0563] In one embodiment of the methods provided above, the treatment comprising administration of Factor VIII is assigned to an individual with a predicted decreased risk of 20 developing antibodies against Factor VIII.

[0564] In one embodiment of the methods provided above, the treatment comprising Factor VIII bypass therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0565] In one embodiment of the methods provided above, assigning treatment comprises adjusting a dosage and/or frequency of Factor VIII administration based on the predicted risk of developing antibodies against Factor VIII.

255

WO 2011/131774

PCT/EP2011/056471 [0566] In one embodiment of the methods provided above, adjusting a dosage of Factor VIII comprises increasing the dosage and/or frequency of Factor VIII administered to an individual ^H with a predicted decreased risk of developing antibodies against Factor VIII.

[0567] In one embodiment of the methods provided above, adjusting a dosage of Factor VIII comprises decreasing the dosage and/or frequency of Factor VIII administered to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0568] In one embodiment of the methods provided above, assigning treatment comprises adjusting a dosage and/or frequency of a non-Factor VIII hemostatic agent administration based on the predicted risk of developing antibodies against Factor VIII.

[0569] In one embodiment of the methods provided above, adjusting a dosage of a non-Factor

VIII hemostatic agent comprises decreasing the dosage and/or frequency of a non-Factor VIII hemostatic agent administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII.

[0570] In one embodiment of the methods provided above, adjusting a dosage of a non-Factor

VIII hemostatic agent comprises increasing the dosage and/or frequency of a non-Factor VIII hemostatic agent administered to an individual with a predicted increased risk of developing antibodies against Factor VIII.

[0571] In one embodiment, the present invention provides an oligonucleotide from 10 to 60 nucleotides in length that contacts at least one single nucleotide polymorphism (SNP) selected from the group consisting of the SNPs listed in Table 1.

[0572] In one embodiment, the present invention provides a diagnostic kit for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the kit comprising at least one oligonucleotide capable of being used to detect at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP 25 listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4.

[0573] In one embodiment of the diagnostic kits described above, the SNP is selected from the group consisting of rsl2368829, rsi 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712.

256

WO 2011/131774

PCT/EP2011/056471 [0574] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs 12368829.

[0575] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rsi 1744216.

[0576] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rsi863993.

[0577] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs4147385.

[0578] In one embodiment of the diagnostic kits described above, the kit comprises an 0 oligonucleotide capable of being used to detect SNP rs 12546235.

[0579] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs4242389.

[0580] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs 10054825.

[0581] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs 17535213.

[0582] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs 10072056.

[0583] In one embodiment of the diagnostic kits described above, the kit comprises an 20 oligonucleotide capable of being used to detect SNP rs 17725712.

[0584] In one embodiment, the present invention provides a diagnostic kit for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with severe Hemophilia, the kit comprising at least one oligonucleotide capable of being used to detect at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP 25 listed in Table 2 and a SNP listed in Table 4.

[0585] In one embodiment of the diagnostic kits described above, the SNP is selected from the group consisting of rsl2368829, rs4147385, rsi 1744216, rsl863993, rsl7535213, rsl0072056,

257

WO 2011/131774

PCT/EP2011/056471 rs 10054825, rs 12546235, rs4242389, rs2071336, rs414634, rs 17725712, rsl 1773821, rs8005905, and rs9482888.

[0586] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs 12368829.

[0587] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs4147385.

[0588] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rsl 1744216.

[0589] In one embodiment of the diagnostic kits described above, the kit comprises an 0 oligonucleotide capable of being used to detect SNP rsl863993.

[0590] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs 17535213.

[0591] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs 10072056.

[0592] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs 10054825.

[0593] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs 12546235.

[0594] In one embodiment of the diagnostic kits described above, the kit comprises an 20 oligonucleotide capable of being used to detect SNP rs4242389.

[0595] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs2071336.

[0596] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs414634.

[0597] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs 17725712.

[0598] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rsl 1773821.

258

WO 2011/131774

PCT/EP2011/056471 [0599] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs8005905.

[0600] In one embodiment of the diagnostic kits described above, the kit comprises an oligonucleotide capable of being used to detect SNP rs9482888..

[0601] In one embodiment of the diagnostic kits described above, the oligonucleotide flanks the position of the SNP in the genome.

[0602] In one embodiment of the diagnostic kits described above, the oligonucleotide overlaps the position of the SNP in the genome.

[0603] In one embodiment, the present invention provides a microarray for predicting the risk 0 of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with

Hemophilia, the microarray comprising a support having a plurality of discrete regions, each discrete region having a nucleic acid fragment spotted thereon, wherein at least one nucleic acid fragment spotted on the support comprises a sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) selected from the group consisting 5 of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in

Table 4.

[0604] In one embodiment of the microarrays described above, the SNP is selected from the group consisting of rsl2368829, rsl 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712.

[0605] In one embodiment, the present invention provides a microarray for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with severe Hemophilia, the microarray comprising a support having a plurality of discrete regions, each discrete region having a nucleic acid fragment spotted thereon, wherein at least one nucleic acid fragment spotted on the support comprises a sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4.

[0606] In one embodiment of the microarrays described above, the SNP is selected from the group consisting of rsl2368829, rs4147385, rsl 1744216, rsl863993, rsl7535213, rsl0072056, rs 10054825, rs 12546235, rs4242389, rs2071336, rs414634, rs 17725712, rsl 1773821, rs8005905, and rs9482888.

259

WO 2011/131774

PCT/EP2011/056471 [0607] In one embodiment of the microarrays described above, the sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) ^H includes a nucleotide corresponding to the position of the SNP in the genome.

VI. Examples

Example 1 [0608] The following example is offered to illustrate, but not to limit, the claimed invention.

[0609] Through a collaboration among three multi-center studies: the Hemophilia Inhibitor Genetics Study (HIGS), the Malmo International Brother Study (MIBS), and the Hemophilia 0 Growth and Development Study (HGDS), a combined cohort was formed to conduct an association study to test the hypothesis that antibody development to FVIII is mediated by immune response and immune modifier genes. The HIGS study population (N=295) was composed of brother pairs concordant for a history of inhibitors, or discordant (one with an inhibitor, the other without); and a group of singletons with inhibitors. Participants from Europe 5 and North America accounted for 43% and 57% of the HIGS population, respectively. The

MIBS study population (N=120) was composed of brother pairs with hemophilia with or without inhibitors, recruited primarily from centers in Europe. The HGDS (N=265) is a populationbased longitudinal investigation conducted in 14 US hemophilia treatment centers. Together, these studies make up the HIGS Combined Cohort and included clinical and laboratory data for 20 680 people with hemophilia A.

[0610] Using the Illumina iSelect® platform, 14,626 single nucleotide polymorphisms (SNPs) from 1,081 genes were typed. These genes included immune response and immune modifier genes, including cytokines and their receptors, chemokines and their receptors, pathway gene involved in inflammatory and immune responses, and human leukocyte antigen (HLA) gene 25 complex genes. The SNPs were selected using an algorithm to maximize information content and minimize the number of SNPs/gene. All regulatory and nonsynonymous (codon-changing) SNPs within a gene were chosen, as well as haplotype tagging SNPs, using stringent criteria to avoid SNPs that are non-independent.

260

WO 2011/131774

PCT/EP2011/056471 [0611] The statistical analysis was completed among the total group (N=680). Models were adjusted for population substructure, severity of hemophilia, type of factor VIII gene mutation ^H (high vs. low risk), year of birth, and geographic region (Europe/North America). Meta-analyses were used to obtain single odds ratios (OR) and p-values for the three cohorts.

[0612] Eighty-five percent of the HIGS Combined Cohort had severe (<0.01 lU/mL) hemophilia; 10% had moderate (0.01 - 0.05 lU/mL) hemophilia; and 4.4% had mild (>0.05 - 0.4 lU/mL) hemophilia. The cohort was predominately of European descent, 81.0%, with 6.2% of African descent, 8.8% Hispanic, and the remaining 4% of other races and ethnicities. Forty-nine percent of the cohort had, or had a history of, an inhibitor >1 BU.

[0613] A total of 13,952 of the 14,626 (95.4%) SNPs were successfully genotyped. One hundred fourteen were associated with inhibitor status at the p<0.0l level (Table 1). Strong SNP associations for the total group were observed in the DOCK2 (rsl 1744216, OR 0.28, p= 0.00004; and rsl863993, OR 3.9, ^=0.0002), MAPK9 (rs4147385, OR 2.0, ^=0.0003), F13A1 (rsl3206518, OR 0.32, ^=0.00007), CD36 (rs3211834, OR 0.56,^=0.0002), and PTPRR (rsl567748, OR 0.51, p=Q.0003) genes (Table 1). For four markers located within the MAPK9 (rs4147385), DOCK2 (rsl 1744216 and rsl863993), and CD36 (rs3211834) genes, the associations were similar, or stronger, for the subgroup with severe hemophilia (Table 2). For the subgroup with severe hemophilia, a strong association with inhibitor development was found for the SNP rs4147385, a C>T variant in an intronic region of the MAPK9 gene (OR 2.3, p=Q.00003); for the SNP rsl 1744216, a C>G variant in an intronic region of the DOCK2 gene (OR 0.30, p=Q.00008); for the SNP rsl863993, a C>T variant in an intronic region of the DOCK2 gene (OR 4.4, j>=0.0009); and for the SNP rs3211834, a A>C variant in an intronic region of the CD36 gene (OR 0.59, p=Q.0008).

Example 2 [0614] In order to further validate the findings in Example 1, additional samples were collected and analyzed for the presence of SNPs associated with the formation of Factor VIII autoantibody inhibitors in patients with mild, moderate, and severe Hemophilia. As above, a combined cohort was formed from three multi-center studies: the Hemophilia Inhibitor Genetics Study (HIGS), the Malmo International Brother Study (MIBS), and the Hemophilia Growth and Development

Study (HGDS), to conduct an association study to test the hypothesis that antibody development to FVIII is mediated by immune response and immune modifier genes. In total, samples from

261

WO 2011/131774

PCT/EP2011/056471

774 patients diagnosed with Hemophilia, 674 of which were diagnosed with severe Hemophilia, were used for the meta-analysis.

[0615] Using the Illumina iSelect® platform, 14,626 single nucleotide polymorphisms (SNPs) from 1,081 genes were typed. These genes included immune response and immune modifier genes, including cytokines and their receptors, chemokines and their receptors, pathway gene involved in inflammatory and immune responses, and human leukocyte antigen (HLA) gene complex genes. The SNPs were selected using an algorithm to maximize information content and minimize the number of SNPs/gene. All regulatory and nonsynonymous (codon-changing) SNPs within a gene were chosen, as well as haplotype tagging SNPs, using stringent criteria to avoid SNPs that are non-independent.

[0616] Genotype data were obtained for the entire, combined cohort on the Illumina iSelect panel composed of 14,626 polymorphic markers. Testing for missingness (>20% missing), low minor allele frequency (<0.01) and a departure from Hardy Weinburg equilibrium (p<0.001), left 13,394 markers for analysis. The analysis was carried out separately for each of the three study cohorts; HGDS, MIBS and HIGS. Using the markers that passed QC, principal components were constructed to account for population admixture. Because of the different distributions of related individuals in each cohort, different models were used to analyze the data. The HGDS individuals were analyzed with logistic regression, MBS with GEE and HIGS with alternating logistic regression. Covariates included severity of hemophilia, year of birth, the first three principal components to account for admixture, and mutation risk in the case of MIBS and HIGS and an indicator of presence of factor VIII gene inversion for HGDS. The primary hypothesis test was carried out on the predictor for each SNP which was modeled as additive or specifically the number of minor alleles in each individual. Additionally the models were rerun on only the individuals with severe hemophilia. Once each estimate and standard error was obtained for 25 each cohort model on each SNP, they were combined in a meta analytic technique summing the estimates weighted by the standard errors. A new standard error was also calculated which allowed Z statistic to be constructed and tested for the total combined cohort.

[0617] The statistical analysis was completed among the total group (N=774), as well as among patients diagnosed with severe Hemophilia (N=674). Models were adjusted for 30 population substructure, severity of hemophilia, type of factor VIII gene mutation (high vs. low

262

WO 2011/131774

PCT/EP2011/056471 risk), year of birth, and geographic region (Europe/North America). Meta-analyses were used to obtain single odds ratios (OR) and p-values for the three cohorts.

[0618] A total of 13,394 of the 14,626 (91.6%) SNPs were successfully genotyped. Two hundred and sixteen were associated with inhibitor status at the p<0.01 level (Table 3). Strong

SNP associations for the total group were observed in the CCDC41 (rs 12368829, OR 0.27, p=5.08E-07); DOCK2 (rsi 1744216, OR 0.31, p=3.56E-06; and rsl863993, OR 3.89, p=8.36E05); MAPK9 (rs4147385, OR 2.14, p=9.22E-06); TNFRSF10C (rs 12546235, OR 0.43, p=l.HE05; and rs4242389, OR 0.50, p=0.000113642); IQGAP2 (rsl0054825, OR 0.37, p=2.21E-05); PUS7L (rsl7535213, OR 0.57, p=4.02E-05); PDGFRB (rsl0072056, OR 0.61, p=5.84E-05); and

CSF1R (rsl7725712, OR 2.51, p=0.000165351) genes.

[0619] Strong SNP associations for the severe Hemophilia group were observed in the CCDC41 (rsl2368829, OR 0.25, p=1.81E-07); MAPK9 (rs4147385, OR 2.44, p=1.08E-06); DOCK2 (rsi 1744216, OR 0.32, p=5.86E-06; and rsl863993, OR 4.33, p=0.000159); PUS7L (rsl7535213, OR 0.54, p=1.04E-05); PDGFRB (rsl0072056, OR 0.57, p=1.05E-05); IQGAP2 (rsl0054825, OR 0.37, p=1.10E-05); TNFRSF10C (rsl2546235, OR 0.44, p=1.64E-05; and rs4242389, OR 0.50, p=0.000128788); TNFRSF17 (rs2071336, OR 0.27, p=0.000106); BLM (rs414634, OR 1.72, p=0.000124); CSF1R (rsl7725712, OR 3.00, p=0.000124); PTPRN2 (rsll773821, OR 0.51, p=0.000130); HSP90AA1 (rs8005905, OR 0.48; p=0.000132); and PTPRK (rs9482888, OR 10.75, p=0.000182) genes.

Example 3 [0620] The risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with Hemophilia A may be determined by detecting one or more SNPs disclosed herein. To do this, a capture probe set comprising oligonucleotides capable of distinguishing the nucleotide present at the SNP position may be attached to a solid support to create an oligonucleotide array. For example, probes capable of detecting the set of SNPs listed in Table 5 are used to create a microarray. Nucleic acid (i.e., genomic DNA, cDNA, mRNA, etc.) is isolated and/or amplified from a biological sample taken from the individual and subsequently hybridized to the array using hybridization techniques well known in the art. The identity of the nucleotides present at the 24 SNP genomic positions shown in Table 5 can then be determined using detection/analysis techniques also well known in the art. Alternatively, the presence or absence of the SNP of interest can be determined using the same well known techniques.

263

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 [0621] The results of the SNP detection described above, can then be used to predict a risk for the development of Factor VIII inhibitor antibodies in the individual. For example, the detection of rs 12368829 in the sample is predictive of a significantly decreased risk of developing Factor VIII inhibitors. Similarly, the detection of both rs4147385 and rs927335 is predictive of a significantly incresed risk of developing Factor VIII inhibitors.

[0622] Likewise, detection of one or more SNPs listed in Table 5 may be achieved by performing one or more RT-qPCR reactions. In this case, individual RT-qPCR reactions or multiplex RT-qPCR reactions may be performed to identify the nucleotides present at the genomic locations of the SNPs listed in Table 5, or to detect the presence or absence of the SNPs 0 listed in Table 5, using techniques well known in the art. The data provided by these assays may then be used to provide a risk for the development of Factor VIII inhibitor antibodies in the individual.

[0623] Any probe set may be used, comprising capture probes capable of detecting between 1 and all of the SNPs listed in Tables 1 to 4. The probe sets may further comprise internal controls, additional probes useful for providing further predictive power, and/or unrelated probe sets.

Table 5.

SNP	Gene	Meta Odds	Meta P
rsl2368829	CCDC41	0.27311013	5.08E-07
rsl1744216	DOCK2	0.30667899	3.56E-06
rs4147385	MAPK9	2.13745578	9.22E-06
rs12546235	TNFRSF10C	0.43388002	1.11E-05
rsl0054825	IQGAP2	0.3743547	2.21E-05
rsl7535213	PUS7L	0.57027044	4.02E-05
rsl0072056	PDGFRB	0.60837768	5.84E-05
rsl863993	DOCK2	3.88981038	8.36E-05
rs4242389	TNFRSF10C	0.49632251	0.00011364
rsl7725712	CSF1R	2.50759989	0.00016535
rsl1773821	PTPRN2	0.54041127	0.00033105
rs414634	BLM	1.62246205	0.00033946
rsl882019	HSP90B1	0.53629298	0.00034044
rsl3206518	F13A1	0.39427174	0.00035099
rs927335	CD44	1.69891458	0.00036195
rs6482644	PTPRE	0.57798945	0.00040403
rs4077341	TNFRSF10C	0.63448794	0.00042665
rsl884564	LOC728018	0.55434198	0.00051894
rs3826392	MAP2K4	0.6309839	0.00053597

264

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

rs390406	CFC	0.56597223	0.00053686
rs440238	PTPRD	0.62008121	0.00057369
rs9482888	PTPRK	6.50375409	0.00058077
rs2596606	NFATC1	1.75806233	0.00058124
rsl7652304	IQGAP2	3.55426184	0.00062941

Example 4 [0624] The results obtained in the previous example may then be used to direct or modify a course of therapy in the individual. For example, the detection of SNP rs 12368829, which is predictive of a decreased likelihood of the development of Factor VIII inhibitor in response to Factor VIII therapy, may lead a physician to assign a course of treatment comprising administration of FVIII to the individual. Conversely, the detection of SNPs rs4147385 and rs927335, which is predictive of an increased risk of developing Factor VIII inhibitor antibodies in response to Factor VIII therapy, may lead a physician to assign a course of treatment comprising administration of a non-FVIII hemostatic agent (i.e., FVIII bypass therapy). Alternatively, after the detection of both rs4147385 and rs927335, a physician may assign a course of treatment comprising administration of both Factor VIII and a non-FVIII hemostatic agent. In this manner, combination therapy may more effective than administration of either Factor VIII or a non-FVIII hemostatic agent alone. For example, the development of anti-FVIII inhibitory antibodies results in the reduced efficacy of FVIII administration, at which point the non-FVIII hemostatic agent may supplement this deficiency.

[0625] Although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, one of skill in the art will appreciate that certain changes and modifications may be practiced within the scope of the appended claims. In addition, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference. Where a conflict exists between the instant application and a reference provided herein, the instant application shall dominate.

265

WO 2011/131774

PCT/EP2011/056471

Tabl

Meta P

4.09ΕΌ5

6.93Ε-05

0.000226

0.000238

CN O O O ό

0.000261

cn o o o ό

0.000327

0.000447

0.000508

LD CO O O o ό

00 o o ό

0.001504

0.001599

0.001635

0.001637

0.001786

00 cn o o ό

0.002123

0.002241

0.002276

0.00229

0.002331

(/)

00

px

,_|

px

^-1

Ρχ

Ρχ

cn

00

1 n

Ch

σ

( 1

ZTL

Ch

px

I D

CN

Ch

CN

1 n

Ch

m

r)

ID

cn

px

Ό

00

pX,

lu

CN

m

00

I o

fT\

cn

ω

CN

(T

ID

1

l f)

m

I f(

CN

Q

ι Ο

l f)

σι

ι n

cn

f 1

in

CN

CN

00

00

o

p^

00

l

ΟΊ

00

’d-

m

ς—|

00

Ch

j—|

ω

co

ω

CN

LD

1

ps.

LD

CN

cn

p^

LU

(u

ω

CN

cn

Ch

Ln

00

cn

cn

00

CO

CN

LD

00

cn

00

CN

cn

00

LD

()

px.

00

c)

CN

LD

LD

cn

LD

( )

px,

m

LD

LU

m

CN

Ch

Ch

cn

m

LD

LD

LD

CN

LD

LD

I

LD

LD

LD

px

ό

6

cn

ό

cn

t-l

t-l

6

6

6

t-l

6

cn

6

ό

CN

6

6

6

6

t-l

ό

ό

Γθ

LD

LD

Ln

Ch

Ch

cn

CN

LD

ld

CN

CN

ID

px

CN

lo

Cf)

CN

Γ'·'··

Ο

o

ω

CO

LD

O

CN

o

LD

00

lD

Ch

L/l CQ

LU

LU

id

o

CN

00

LU

(D

cn

O

δ

CN

cn

1 n

Ο

L_J

(-)

Ο

LD

00

n

Ο

px.

Ο

LD

CN

Γ)

cn

O

px.

px.

px

2

m

σι

LL)

1

ω

m

ω

,-1

00

co

ω

o

ω

p~~

ω

CN

ω

o

ό

rf)

cfj

ό

ό

ό

ό

ό

ό

CN

ό

ό

ό

ό

ό

ό

ό

ό

ό

ci

ό

ό

ό

<Λ

η

00

00

^n

m

Ch

00

Ch

1 H

Ρχ

1 D

00

px,

CT»

^*n

m

cn

m

Ο

ι ο

1

LD

00

CN

m

I H

(-)

m

p^.

ω

I A

(

ι n

00

CM

m

Ο

m

00

o

px,

σι

^p

Ch

Ch

px,

LD

LD

( )

(

c ι

cn

LD

LD

ω

Ο

,—|

1

1

CN

cn

CN

m

o

cn

CN

CN

px,

LD

CN

CN

ω

cn

00

LD

00

CN

LD

00

00

cn

m

cn

cn

LD

cn

px.

LD

px

00

CJ

O

LD

px

|

( )

LD

00

CN

00

CN

CN

cn

CN

pX,

cn

( Ί

LD

LD

cn

CN

00

m

τ—|

ΓΧ

LD

cn

in

LD

CN

LD

CN

cn

px

00

m

LD

LD

LD

LD

CN

6

ό

m

ό

cn

6

ό

6

6

6

6

cn

6

ό

CN

6

6

ό

6

Ή

6

6

CN

σι

CM

^-1

ch

^-1

cn

cn

LD

cn

cn

cn

m

px

cn

cn

LD

cn

,_|

cn

0.

00

Ρχ

CN

Ln

px

( o

Px

M-

cn

CN

ρχ

ρχ

CN

m

00

(

00

cn

00

00

CN

(Ν

px

(. )

cn

1 Π

cn

px

p*X

LD

o

^-|

c J

ι π

cn

( )

cn

00

,—|

C ·>

00

1 d

rr.

c ·>

Ch

m

LD

fNl

ω

00

LO

00

p-χ

m

ι n

ΓΝΙ

φ

(1

ΓΧ|

CN

cs

LD

f >

f 1

m

f ·>

< )

m

cn

CN

CN

pX

LD

f >

Ch

ζ

ω

ω

m

o

Ln

ω

ω

m

ω

ω

lD

o

o

I

ω

ω

ω

o

I

ω

ω

ό

ό

ό

ό

ό

o

ό

o

ό

ό

ό

ό

ό

ό

ό

ό

ό

ό

ό

ό

ό

ό

ό

00

00

m

LD

ID

,_|

ID

ι η

co

n

Ρχ

cn

m

n

^n

m

m

m

Γ\Ι

00

m

¢-1

CN

px

ΓΤ)

00

ι n

( T

CN

1

CN

m

cx|

ι n

CN

m

CN

¢-1

l Γ)

00

px,

l

cn

(·>

p^

ι H

1

CN

00

m

px.

I f(

pX

Ln

σ

ι n

Ch

CN

m

I f)

CN

cn

LU

pX,

,—|

LD

ch

cn

LD

( Ί

LD

px,

px,

m

( Ϊ

cn

CN

LD

<Λ

ld

1

LD

Ch

px.

00

m

CN

px,

,—|

LD

LD

f )

Φ

CN

00

CN

LD

00

m

CN

()

CN

00

CN

cn

00

( )

LD

CN

m

00

00

CO

LD

00

LD

LD

LD

00

LD

LD

LD

LD

LD

J.

6

6

CN

ω

Ή

CN

CN

o

6

6

CM

6

Ή

6

o

6

6

6

6

Ή

ω

ω

ο

Ch

Ch

ι n

n

ι Π

^_|

LD

CN

00

1 fl

m

1 n

CN

cn

1 n

LD

ο

Ch

1 A

Ln

px.

Ch

1 D

,—|

CO

LD

f-J

C )

LD

cn

,—1

m

00

< ο

4Λ

σ>

1 f)

CN

LD

CN

00

1

m

cn

ι n

( )

ι n

Ch

px

CN

00

CN

( )

ι η

Q

ω

tD

1

CO

1

CN

o

(Ο

CN

px

CN

LD

Ch

px.

00

CN

<)

ίΠ

px

1

rn

o

ΓΧ.|

m

( )

LD

Ch

CN

px

cn

* n

1

CN

ι η

τ—|

tD

px

v-|

o

o

ω

,—|

o

cn

ω

px

ω

ω

O

I

ω

o

ω

ό

ό

ό

6

ό

ό

ό

o

ό

o

ό

ό

ό

ό

ό

ό

ό

ό

ό

ό

ό

ό

ό

<Λ

m

CN

CN

,_|

m

Pv.

LD

Ch

,_|

co

,_|

00

m

00

1 H

LD

cn

cn

LD

LD

Γ(

ld

px

LD

CN

Ch

1 D

ι Λ

m

00

()

CN

px.

ι n

cn

< t

C >

ι D

C )

Ch

ι n

m

I A

px

00

* n

Ch

00

< 1

LD

00

LD

px.

ω

CN

m

pX

ο

Ο

CN

CD

LD

D|

px

m

ι A

CN

00

00

m

cn

ps.

1 O

ι D

px

(✓)

ID

00

ch

p^.

ID

00

Ch

ι Η

fTs

* n

m

00

o

00

ι D

rn

CN

p^.

ID

Q

CN

m

Ln

ω

f 1

1

ι Η

CN

CN

CN

cn

px.

CN

00

l O

CN

(D

CN

LD

ω

cn

o

If)

to

Ch

ω

LD

,—|

cn

CN

LD

Px

LD

ω

px

LD

X

6

ό

tH

6

m

CN

CN

tH

6

6

tH

Ή

tH

ό

CN

6

ό

6

ό

CN

6

6

Gene

D0CK2

F13A1

F2R

CD36

D0CK2

z

MAPK9

PTPRR

CD36

PTPRE

5 ______1 CD

PDGFRB

IQGAP2

PTPRR

PCGF2

CSF1R

PTPRN2

PTGES

PTPRN2

ELOVL6

IQGAP2

TNFRSF10

ELOVL6

c

c

c

o

o

o

C

c

c

c

c

c

c

c

c

c

C

c

c

r>n

0D

c

c

c

nn

c

c

□

ο

Ο

o

o

Q

o

o

o

o

o

o

o

o

o

ω

Φ

o

o

o

0J

o

o

W)

(Ό

(Τ

φ

C

f—

f—

C

Q

Q

f—

f—

f—

f—

Q

Q

(Λ

(/)

f—

f—

C

Q

(Λ

Q

C

0ί

D

·—

·—

D

—

Ε

_o

_O

_O

ΒΡ

169018841

6098001

o o 00 Ln o

80118053

169142758

112282428

179610123

69360997

80116499

129715311

89157257

149485499

75912949

69318052

34143085

149471001

157343101

131541702

157639794

111189034

75924224

23018464

111190938

Ε ο

CN

o

ld

CN

px

Ch

00

£

SNP

L1744216

L3206518

CN 00 CN CN

3211834

1863993

(910682

4147385

1567748

3211821

6482644

>414634

L0072056

L7652304

2584019

2879097

L7725712

L2667537

2302821

o

6837303

3736395

L2546235

4698806

I ο

Γ /)

ω

(/)

(/)

L_

(Λ

(Λ

(Λ

s___

(Λ

(/)

Γ /)

Γ Cl

(Λ

(Λ

(Λ

ίθ

>-

=—

266

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

<u	Meta P	0.002334	0.002391	rxi O O 0	0.002461	0.002555	0.002641	0.002769	0.002927	0.002956	0.002991	0.003155	0.003241	0.003253	0.003296	0.003382	0.003529	0.003691	0.003698	0.003793	o o o ό	0.004506	0.004739	0.004784	0.004812
Meta Odds	1.75194031	1.59756682	0.57273836	0.36386724	1.71913266	0.59591265	0.65622124	0.62569985	0.6451481	1.78756484	2.24773698	0.55485629	1.73195975	0.62828413	1.87206666	0.64621499	0.52284161	0.55604255	0.6347428	0.57482385	0.60927983	1.54973639	1.72576938	0.54856423
MIBSP	0.150491	0.076666	0.054693	0.565263	0.075126	0.023529	0.44484	0.159352	0.099584	0.063497	0.283547	0.818363	0.395289	0.289683	0.051301	0.09436	0.113562	0.190505	0.124866	0.231062	0.250577	0.371962	0.2763	0.455405
MIBS Odds	1.72391	1.680531	0.5181073	0.4908602	1.7904536	0.4132124	m rn o o 00 ό	0.5921131	0.5689053	2.4037715	1.7183641	1.1098003	00 Ln 00 cn	0.6858094	2.047579	0.5588144	0.3971541	0.4970193	0.5529907	0.611059	0.6270542	1.3503939	1.5093295	1.5707582
HIGSP	0.160159	0.499644	0.084364	0.006238	Ln o 00 o o ό	0.003215	0.006524	0.138587	δ 00 rxi O ό	0.024548	0.267218	0.000972	0.022255	0.249509	0.197508	0.081574	0.151245	0.023356	0.226668	0.078361	0.086562	0.018214	δ δ ό	rn o o o ό
HIGS Odds	1.53252391	1.17341603	0.61933994	0.29631921	2.31479609	0.47128413	0.55152593	0.71389667	0.60957915	2.02440479	1.66803937	0.36355189	2.16608728	0.78060758	1.61477947	0.68927979	0.66017337	0.52939193	0.76091128	0.63129779	0.65212624	1.78509969	2.4197051	0.33763134
HGDSP	0.017929	0.002205	0.107265	0.234687	0.459588	0.809522	0.185484	0.020616	0.278122	0.260212	0.003824	0.239964	0.05504	0.001385	0.067518	00 00 CD o CD o ό	0.018361	0.214628	0.015662	rxi O rn o ό	0.046424	0.16464	0.156645	0.512999
Tabl	HGDS Odds	2.0142888	2.3878022	0.5586063	0.4982842	1.2490102	1.0767496	0.7208544	0.5295218	0.7552154	1.4043985	3.8641862	0.6675452	1.8412808	0.3654781	1.9891348	0.6342569	0.3438183	0.6379987	0.5229615	0.425719	0.5365861	1.4273583	1.5037749	0.7894051
Gene	IQGAP2	IQGAP2	1— or H	PTPRG	YWHAH	PTPRR		2 H	PTPRN2	FBN3	2 H	CLC	NFATC1	PTPRD	ITGA9	TNFRSF10C	CX3CR1	PTPRT	2 H	-	BATS	MR1	PTPRU	STK17A
Region	intron	intron	intron	intron	intron	intron	intron	intron	intron	coding-nonsynonymous	intron	locus-region	intron	intron	intron	intron	locus-region	intron	coding-nonsynonymous		intron	intron	intron	intron
BP	75931035	75942821	40843315	61819146	30671684	69368222	129749982	48077512	157643166	8109328	48086525	44920811	75263804	9006071	37572487	23018293	39279822	40263638	48122843	rxi rxi Ln	31773173	179273553	29488905	43608739
Chrom	Ln	Ln	o rxi	m	rxi rxi	rxi	o		r-	3		3	00	CD	m	00	m	o rxi		rxi	LO			r-
SNP	rsll952962	rs3797390	rsl3042473	rsl3096099	rs7290696	rs949664	ίη CXI rxi LO	rs4752894	rsl0261447	rs7246376	rs4752896	rs390406	rs2596606	rs440238	rsl892803	rs4077341	rs9826296	rs 7348444	rs4752904	rs2305340	rs805274	rsl411479	rs2076620	rs4724231

267

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019

<u	Meta P	00 00 00 o o ό	o o lh o o ό	S0TS00O	0.005195	0.005214	0.005315	0.005454	0.005618	0.005738	00 Ln o o ό	0.005937	96500Ό	0.006042	0.006094	0.006136	0.006153	0.006165	0.00628	0.006377	0.006407	0.006437	0.006451	0.006549	0.006566
Meta Odds	0.57386348	1.51042662	0.64180759	0.62448923	1.84786063	0.59943237	1.71977212	1.64973302	0.54320594	1.69672289	0.37100891	0.53488592	1.79286631	1.72813239	0.57016001	1.89108031	1.8096482	1.46340143	0.66237867	0.62021487	0.66309631	1.51376079	00 00 Ln	0.49784173
MIBSP	0.260186	0.028269	0.122106	0.658978	cn O ό	0.059969	0.290559	0.141189	60055Ό	0.003379	0.565263	0.46717	0.013791	00 cn cn o ό	0.039454	0.331614	0.467913	0.033866	0.041857	0.096451	0.047331	0.022182	o o ό	0.191761
MIBS Odds	0.5863538	1.914168	0.5978915	0.8460937	2.3760572	0.5213094	1.6525984	1.5375034	0.6554991	3.368561	0.4908602	0.6579718	3.7963966	2.1946518	0.4658273	1.7018946	0.6946357	1.7877334	0.4853325	CD O O 00 ό	0.4946616	2.5238917	2.6856314	0.4692903
HIGSP	0.000385	0.925697	0.002654	0.019916	0.135263	0.092772	0.1795	0.293217	0.003914	0.790802	00 cn o ό	0.050965	0.435285	0.353439	0.125724	σί 00 ό	0.033909	0.021344	0.036045	00 o cn o o ό	0.065168	0.328324	0.842582	0.032168
HIGS Odds	0.33725774	0.97944148	0.48112775	0.57030552	1.74929637	0.63343863	CD 00 O 00	1.78487827	0.43008835	0.92879429	0.39759991	0.55684704	1.30128893	1.34817589	0.63615624	1.33683346	2.09461214	1.6604675	0.6199714	0.66019694	0.65968842	1.23849185	0.9359476	0.45971894
HGDSP	0.739882	0.00152	0.929397	555860Ό	0.206536	0.213699	0.015115	0.03429	0.666134	0.004271	0.084428	0.062242	0.054544	0.073469	0.25287	0.006262	CD 00 O o ό	0.82636	0.490258	0.164847	0.310137	0.052845	0.03148	0.293327
Tabl	HGDS Odds	1.1146267	2.2927241	1.0252831	0.5959129	1.5913304	0.6323805	1 2.3112244	1.7103053	0.8374258	2.6815501	0.2706226	0.4255593	1.846775	1.8809113	0.5921978	2.4731734	2.4191263	1.0554308	0.8410174	0.634111	00 o CD O ό	1.6260816	2.134554	0.6014832
Gene	PPP2R2B	-	PTPRR	MR1	PPP3CC	1— or H	CNTFR	Qi Ϊ—	IFI44	PTPRK	PTPRG	CX3CR1	F13A1	ITGA9	HSP90B1	CD247	OSMR	00 CD	EGF	GAB2	2 H	IGF1R	PTPRK	ITGB2
Region	intron		intron	intron	intron	intron	intron	intron	coding-nonsynonymous	intron	intron	locus-region	intron	intron	intron	intron	intron	intron	intron	mrna-utr	intron	intron	intron	intron
BP	146106438	20926259	69330069	179279594	22441022	40836321	34556190	00 00 o 00 cxl	cn CD 00 00 00 00	128405416	61805637	39279468	6186280	37557606	102861797	165735488	38917360	18513844	111131016	77604417	48118881	97101441	128491712	45161993
Chrom	lh	cxl cxl	CXI		00	o cxl	CD	cn cxi		LO	cn	cn	LO	m	CXI		Ln	2				Ln	LO	ex!
SNP	rs7715375	rs7289754	rsl2310405	rs3845422	rsl7671456	rsl885831	rs4472605	rs5743740	rs2070123	rs2179694	rs6782288	rsl877563	rsl781795	rs9862163	rsl882019	rs704853	rs2278324	rsl0854166	rs7692976	rsl046780	rs7124275	rsl007212	rs4498385	rs3788151

268

WO 2011/131774

PCT/EP2011/056471

Tabl

Meta P	S6S900O	0.006611	0.006639	0.006711	0.00682	0.007013	0.007139	o o ό	0.007211	δ Ln o o ό	0.007528	0.007586	0.007641	0.00772	0.007793	0.007819	m 00 o o ό	0.007938	0.007957	0.007992	Γ0800Ό	o 00 o o 6	0.008131	0.008228
Meta Odds	0.64372536	0.63788244	0.67581779	0.37611586	0.57034852	1.71795081	0.65567615	1.82790198	0.63787515	1.63232737	1.52347214	1.55829502	3.48147191	0.52374625	1.53591151	0.68159392	0.64167123	0.60077721	2.03268322	2.49550151	1.49787227	1.59400528	0.60235771	1.586918
MIBSP	0.036943	0.357161	0.00172	0.037285	0.193474	0.001012	0.213678	0.003556	0.142653	0.125114	0.587461	0.044995	0.227197	0.193943	0.033397	in ό	0.030721	0.284326	0.163324	0.211151	0.633993	0.028862	0.866827	58666Ό
MIBS Odds	0.4781692	0.7295119	0.366263	0.2422667	0.5347065	3.7147925	0.6631102	2.5838069	0.6589784	1.6738235	1.2172621	2.3356971	0.1594134	0.4329791	2.3160284	0.7897393	0.377223	0.6112004	1.8293887	2.8928281	0.8473802	2.0670691	0.9280367	0.9999378
HIGS P	cn 00 o o ό	0.015021	0.146873	0.126849	8SS6T0O	0.61948	0.006163	0.043275	0.574219	0.773011	0.038224	0.232658	0.127892	0.119365	0.14235	0.014751	0.004238	0.050925	00 co o ό	0.226386	0.001996	0.53873	0.002456	0.043789
HIGS Odds	0.51108839	0.55397606	0.72923281	0.4881357	0.49711568	1.16603425	0.52107784	2.67055752	0.86725251	1.12015933	1.66998021	1.34681946	4.97171931	0.60641377	1.40690529	0.57036831	0.51499115	0.57644926	3.44089991	2.51750425	2.12394507	1.19553817	0.43685707	1.89566945
HGDSP	0.58352	0.32305	0.590518	0.231422	0.425298	0.205653	0.759767	0.59914	0.001716	0.014414	0.088519	00 o ό	00 o o ό	0.06373	0.198951	0.292013	0.529818	0.158206	0.172178	0.044972	0.218857	0.05877	0.602779	0.019355
HGDSOdds	1.1785056	0.7320953	0.8763896	0.2786922	0.7424757	1.5643264	0.9174485	0.8074122	0.3215836	1.9061049	1.5377377	1.5723055	4.7576862	0.4214185	1.4258451	0.7566059	1.2079285	0.6308068	1.7518657	2.3935609	1.3532686	1.7559848	0.8293457	1.9012346
Gene	PDGFRB	BLM	PTPRE	IGSF2	RAFI	CASP9		<	SRPR	£ H		FCRLA	SYNE2	IQGAP2	CD44	GML	PTPRR	-	2	IL1RAP	PTPRN2	TGFBR2	-	C17orf85
Region	locus-region	intron	intron	intron	intron	intron	intron	intron	intron	intron	mrna-utr	intron	coding-nonsynonymous	intron	ntron	,ntron	ntron		ntron	ntron	intron	ntron		intron
Si	149472648	89113827	129716363	117380273	12680048	15706947	112254016	43299463	125639829	12795499	101317699	159948285	63674348	75837339	35198213	143920893	69338568	30562055	cn LD CM CM CM CM	191740949	157375601	30706286	59022044	3664884
Chrom			o	Ή	m	-1	o			cn CM	CM	1		in		00	pl	to	LD	m	r-	m	CTj	A
SNP	rsll740298	cn o o ω 00 cn cn S_	rs6482647	rs2296449	Ln LO Ln co	rs2020902	rs927010	O cn LTl Cd	rs499205	rs2302267	O	rsll05238	rsl2881815	rsl0054825	CM m m 00 o	LD CH cn 00 cn cn	rsl2831813	8 Ό CM	cn s	rs9817149	rs731305	cn m 00 O cn	rs 10406354	rsl7763453

269

WO 2011/131774

PCT/EP2011/056471

Tabl

Meta P	0.008591	0.008892	0.008925	0.008954	0.009015	0.009026	0.009194	0.009247	0.009281	0.009311	0.009471	0.009474	0.009555	0.009574	0.00968	0.009696	0.009733	0.009809	0.009934
Meta Odds	1.48229265	1.75826409	00 o o o LP	0.68344853	0.60332621	1.67441451	1.56944648	1.48323184	0.64175505	1.88111528	0.64631894	0.60090009	0.68081974	0.63129647	0.63080907	0.67719779	1.4770605	1.48002659	0.6251713
MIBSP	0.753205	0.440595	00 CN 6	0.027298	0.18091	0.062525	0.013612	0.481747	0.091546	00 CN O 0	0.272516	0.204856	0.070661	0.074112	0.315076	0.362499	0.705934	0.127776	0.014247
MIBS Odds	0.9048112	1.4211996	1.2511892	0.4847643	0.5896612	1.8307243	2.4601659	1.3056665	0.5354805	2.4042461	0.6621434	0.5157325	0.562159	0.4848659	0.7020929	0.721396	0.9033077	1.5601867	0.4246379
HIGSP	0.008373	00 CD O 0	0.168684	899Τ6ΤΌ	0.215636	0.22594	0.293626	0.028346	0.04053	0.157439	0.030705	0.002496	0.285671	0.851436	0.027495	666650Ό	0.00231	0.312618	0.152196
HIGS Odds	1.85676739	1.99572072	1.34118139	0.75851277	0.71581985	1.5272999	1.31585407	1.63160741	0.59752742	1.81929094	0.58755828	0.43807445	0.78960669	0.9578572	0.56492416	0.646525	2.28681538	1.27903706	0.67763312
HGDSP	0.093723	0.101125	0.019369	0.204877	0.03055	0.157191	0.204825	0.201171	0.496419	0.4834	0.316431	0.665273	0.0735	CN O O O 0	0.323878	0.131179	CN 00 00 O 0	0.046786	0.539731
HGDS Odds	1.5335318		1.793477	0.7214938	0.4224928	1.6573297	lo	1.3813911	0.8117157	1.3843383	0.7391559	1.1681216	0.6281323	0.2400912	0.7034122	0.6933789	1.5092501	1.6835746	0.8058936
Gene	CD14	PDCD1LG2	LECT2	F13A1	CD69	-	CASP9	UNC13B	PTPRG	PDGFRB	BLM	s < C£	PFDN5	PTPRD	HSP90AA1	IRAK2	KLRF1	SIRPA	PTPRE
Region	intron	intron	intron	intron	intron		intron	intron	intron	intron	intron	intron	locus-region	intron	intron	intron	intron	intron	intron
BP	139993100	5507559	135314336	6191983	9799696	73868986	15699723	35234061	62059196	149486896	89115963	42461605	51979670	9004274	101617977	10223974	9872429	1857920	129641321
Chrom		CD		LO	CN			CD	m	LO	Ln	CN	pj	CD	Pl	m	pj	o CN	o
SNP	rs2569190	00 CD LO ΙΛ	rs31519	rsl267843	CN O LH	rs8064821	rs4646077	rs7851161	rsl983165	rsl0074391	rs7170919	O	rsl465073	rs613613	rs2298877	rsl7815972	rsl2810163	rs2267908	rs7099752

270

WO 2011/131774

PCT/EP2011/056471

Table 2

271

WO 2011/131774

PCT/EP2011/056471

Table 3

Meta P	δ ω ο	3.56E-06	9.22E-06	1.11E-05	2.21E-05	4.02E-05	5.84E-05	8.36E-05	0.00011364	0.00016535	0.00033105	0.00033946	0.00034044	0.00035099	0.00036195	0.00040403	0.00042665	0.00051894	0.00053597	0.00053686	0.00057369	0.00058077	0.00058124
Meta Odds	0.27311013	0.30667899	2.13745578	0.43388002	0.3743547	0.57027044	0.60837768	3.88981038	0.49632251	2.50759989	0.54041127	1.62246205	0.53629298	0.39427174	1.69891458	0.57798945	0.63448794	0.55434198	0.6309839	0.56597223	0.62008121	6.50375409	1.75806233
MIBS P	0.56468936	0.28008697	0.67342809	0.19881566	0.25064205	0.31166083	0.0012715	0.00214385	0.52261252	0.01979588	0.13897121	0.95270754	0.04123021	0.00019143	0.01285391	6.13E-05	0.14814984	0.64569651	0.2022867	0.70671054	0.29007635	0.05718065	0.42621042
MIBS Odds	1.887207952	0.370067427	0.847419164	0.258959962	0.514031922	0.588339124	0.414680192	4.427219418	0.538507051	2.373592311	0.518178068	0.981460036	0.47389969	0.117803784	2.78864964	0.247282655	0.608350511	0.787331851	0.693166599	1.176428114	0.703829319	6.819490938	1.288186948
HIGS P	1.55E-07	1.44E-05	0.00046696	9.63E-06	0.0001897	4.45E-06	0.00074227	0.44319157	8.81E-06	0.01195522	0.0008452	0.00177128	0.00575273	0.02930569	δ o o ό	0.24768847	0.00519201	0.00016232	0.0084676	0.00011495	0.04195541	NA	0.00317447
HIGS Odds	0.23749353	0.27989213	2.46419229	0.37576137	0.324665	0.49318189	0.58186139	1.79012818	0.39817123	2.97352599	0.45675984	1.76721841	0.54596795	0.47126387	1.62199792	0.76981675	0.63450801	0.45784275	0.64374497	0.44814554	0.70059683	0.26952546	2.02654187
HGDS P	0.3719435	0.16683371	0.00015755	0.4523308	0.06709021	0.53836493	0.93339826	0.00889405	0.72881368	0.10166478	0.30225159	0.01250141	0.26821719	0.61761633	0.13592394	0.09490834	0.11146361	0.63023802	0.0470141	0.24554649	0.00171654	0.00413766	0.0500392
HGDS Odds	0.37742656	0.42381549	2.90585493	0.74208	0.42794347	1.24887348	1.02326444	5.4206873	1.15216553	2.22229411	0.73075367	1.9210693	0.6021514	0.7602344	1.49735827	0.63879315	0.65107201	0.8398416	0.50984063	0.67199333	0.3742515	6.37861557	1.8666183
Gene	g	DOCK2	MAPK9	TNFRSF10C	IQGAP2	PUS7L	PDGFRB	DOCK2	TNFRSF10C	CSF1R	PTPRN2	BLM	HSP90B1	F13A1	g	O' H	TNFRSF10C	LOC728018	MAP2K4	CLC	PTPRD	PTPRK	NFATC1
Region	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	locus-region	locus-region	intron	intron	intron
□2	93326073	169018841	179610123	23018464	75837339	42414658	149485499	169142758	23028266	149471001	157648848	89157257	102861797	6098001	35207094	129715311	23018293	1820658	11863629	44920811	9006071	128855804	75263804
Chrom	CM	LD	LD	oo	LD	CM	LD	LD	OO	LD			CM	ID	£	o	OO	o	£		O!	ID	OO
SNP	rsl2368829	rsll744216	rs4147385	rsl2546235	rsl0054825	rsl7535213	rslOO72O56	rsl863993	rs4242389	rsl7725712	rsll773821	rs414634	rsl882019	rsl3206518	rs927335	rs6482644	rs4077341	rsl884564	rs3826392	rs390406	rs440238	rs9482888	rs2596606

272

WO 2011/131774

PCT/EP2011/056471

Table 3

Meta P	0.00062941	0.00064177	0.00068524	0.0006948	0.00072601	0.00079205	0.0008986	0.00092929	0.0009419	0.00102191	0.00102242	0.00106064	0.00107733	0.00109109	0.00109655	0.00112369	0.00114124	0.00117968	0.00122167	0.00126245	0.00128998	0.00131834	0.00132688	0.00132949
Meta Odds	3.55426184	0.62769907	1.78495491	0.60696173	0.52877353	0.63044699	0.43740777	2.92049655	0.6561279	1.89994931	0.6750759	2.15467293	0.65395062	1.52317417	1.51987444	2.18771054	0.58028375	0.36521665	0.6489751	0.61787249	0.64416528	0.57994142	0.62708448	0.6161596
MIBS P	0.0296099	0.29860931	0.42252987	0.18569727	0.44027301	0.72785514	0.08429415	0.00020765	0.00673323	0.41300509	0.2008706	0.04779645	0.14322394	0.07640046	0.61245743	0.01436067	0.233342	0.29502796	0.09253608	0.7473235	0.17368201	0.35425816	0.25304841	0.74236331
MIBS Odds	4.891979443	0.705967504	8860969990	0.609404792	1.414706274	0.885200263	0.23366225	5.68943527	0.459335521	1.445669754	0.688487285	2.060320517	0.597491768	1.840718802	oo o oo oo	2.594822575	0.652465532	0.428886818	0.572171902	0.888862119	0.606535032	0.708220637	0.658007833	0.883688589
HIGS P	0.49335132	0.00175443	0.00282462	0.01306354	0.0003978	Ζ9999900Ό	0.0034416	0.26149332	0.00056846	0.00536715	0.00039605	NA	0.02875229	0.00614501	0.0038546	0.01865724	2.05E-05	5.19E-07	0.03179239	0.00278781	0.00560578	7.72E-06	0.00808487	0.00049546
HIGS Odds	1.64105085	0.58889226	1.89816183	0.62947384	0.45357526	0.64069429	0.43957631	2.20757565	0.56867017	2.17561674	0.57726445	0.43080195	0.70517477	1.57736681	1.61292084	2.59859713	0.38138725	0.10982398	0.69472635	0.56363662	0.62866877	0.36047838	0.61640983	0.52764493
HGDS P	0.00457208	0.27605212	0.01048799	0.05304876	0.03237554	OO o ό	0.54187485	0.67563328	0.19529188	0.08389258	0.95566283	0.00897881	0.03456222	0.34596945	0.10017662	0.49407495	0.35142576	0.23985979	0.06337587	0.10857967	0.30670775	0.27343607	0.15602551	0.59575804
HGDS Odds	4.57533583	0.70729829	2.37666019	0.54648165	0.29750544	0.40531332	0.65304879	1.27420544	1.44908755	1.81397217	0.98642587	2.22338393	0.54309148	1.26889064	1.51571578	1.3729007	1.37885068	1.84576362	0.58664046	0.60462117	0.7297433	OO o oo	0.63701493	0.82036206
Gene	IQGAP2	BLM	OSMR	BAT5	HSP90AA1	PCGF2	DOCK2	F2R	PDGFRB	PDCD1LG2	IL2RA	SLAMF6	PTPRN2	1— CC H	0	PDGFRB	PPP2R2B	TNFRSF17	EL0VL6	MRI	PTPRN2	PPP2R2B	AIRE	VEPH1
Region	intron	intron	intron	intron	coding-nonsynonymous	locus-region	intron	intron	intron	intron	intron	intron	intron	intron	mrna-utr	intron	intron	coding-synonymous	locus-region	intron	intron	intron	intron	coding-nonsynonymous
□2	75912949	89113827	38917360	31773173	101638120	34143085	169394879	76054800	149477865	5507559	6119852	158723751	157343101	40849159	101317699	σ) oo oo σι	146166067	11969175	111189034	179279594	157177926	146189300	44534535	158614482
Chrom	LD		LD	ω	5	£	LD	LD	LD	σι	o			o	rsj	LD	LD	2				LD
SNP	rsl7652304	rs3815003	cn oo I—	rs805274	rs8005905	rs2879097	rs9313487	OO	rs246392	rs6476985	rs7072398	rsl041067	rsl2667537	rs208250	rs6214	rsl0074391	rsl61042	rs2071336	rs6837303	rs3845422	rsl638006	rsl61021	rsl003854	rsl378796

273

WO 2011/131774

PCT/EP2011/056471

Table 3

Meta P	0.00141068	0.00145114	0.00149694	0.00155036	0.00156555	0.00164957	0.00170637	0.00171155	0.00177679	0.00180216	0.00190847	0.00193618	0.00203956	0.00204443	0.00207988	0.00208977	0.00221531	0.00223866	0.00227372	0.00231235	0.00232497	0.00235738	0.00254874	90SSZ00O
Meta Odds	0.65464663	2.10832635	0.63862525	0.63472671	1.69120653	0.64014939	1.67623062	0.64752915	1.68301113	0.67006344	0.65064375	1.65815902	1.6397061	2.90414967	1.60296551	0.62430077	1.6732152	1.35035351	1.7093299	1.64048747	1.53728435	0.6842054	0.6243462	1.66559675
MIBS P	0.45113646	0.01881296	0.24394214	0.02598111	0.53464137	0.35041277	0.0560574	0.00878972	0.0652907	0.00878434	0.41269576	0.97540609	0.23595804	0.00126005	0.0218428	0.64212974	0.59491143	0.01210697	0.12128795	0.01233101	0.07241573	0.3087658	0.60420493	0.09472133
MIBS Odds	0.794312841	2.279926623	0.654104992	0.369125944	1.243594423	0.718400103	2.427149459	0.446458552	2.023094389	0.449778283	0.770807589	1.010710537	1.745523547	7.99520442	1.911456413	0.824326571	1.204884408	1.775653247	1.768951867	2.22598424	1.689002991	1.465610843	1.332110088	1.931419031
HIGS P	0.00843671	NA	0.00547374	0.00026877	0.00918138	0.08378924	0.01577555	0.05307649	0.14102305	0.00452891	0.01057338	0.01033902	0.05529258	0.07353594	0.01771513	0.00290621	0.01007464	0.04939986	0.06345516	0.06374432	0.35032961	0.00245695	0.00162751	0.17646102
HIGS Odds	0.64982994	0.31717254	0.61102113	0.52537558	1.86114844	0.73786157	1.68780469	0.68642326	1.41785272	0.63067265	0.64627154	1.89696314	1.45596316	2.59667403	1.72458275	0.57017516	1.8756407	1.3068943	1.55889951	1.56924172	1.20099738	0.6298167	0.56971475	1.38697287
HGDS P	0.06298351	0.02997707	0.27054948	0.29227446	0.05072084	0.00154964	0.2510527	0.28250053	0.02211585	0.61541149	0.08441604	0.0172052	0.01632828	0.71984049	0.62051063	0.28024405	0.05747238	0.30138287	0.04916586	0.32362484	0.00250135	0.05481569	0.30045815	0.01786271
HGDS Odds	0.53301285	1.9796942	0.71523388	1.36521018	1.82658167	0.357172	oo	0.75832189	1.96820647	1.15547435	0.54254452	1.92846791	2.29595354	1.25796536	1.16018832	0.6947075	1.79952848	1.20558533	2.04564913	1.34340774	2.35975324	0.60087672	0.66417197	2.01317446
Gene	MAP2K4	SLAMF6	BLM	2 H	PKIG	PTPRD	FBN3	MAPK4	IQGAP2	PDGFRB	MAP2K4	C17orf85	CNTFR	1— CC H	LEPREL2		ADA	IL1RAPL2	HDAC4		IQGAP2		1— CC H	IQGAP2
Region	intron	intron	intron	intron	intron	intron	coding-nonsynonymous	intron	intron	intron	intron	intron	intron	intron	locus-region		coding-synonymous	intron	intron	coding-nonsynonymous	intron		intron	intron
□2	11918677	158732980	89115963	48007571	42667504	9004740	8109328	46494835	75931035	149478344	11935497	3664884	34556190	40786436	6805892	15575064	42686329	104690227	239852569	157253101	75942821	30570063	40432747	75924224
Chrom	£			£	o	σι		O0	LD	LD	£	£	σι	o	rs|		o	rn	Csl		LD		o	LD
SNP	rsl2051769	rs3795326	rs7170919	rs7130876	rs244090	rs424051	rs7246376	rsl2959952	rsll952962	rs246394	rsl2325842	rsl7763453	rs4472605	rs926479	rs2071081	rs7690305	rs244076	rs6621980	rs6742576	rs866484	rs3797390	rsl264456	rs6065467	rs3736395

274

WO 2011/131774

PCT/EP2011/056471

Table 3

Meta P	0.00256015	0.00258158	0.00269972	0.00278836	0.00283581	0.00284212	0.00293494	0.00300019	0.00301278	0.00303403	0.00304803	0.00317617	0.00329302	0.0033713	0.00342114	0.00342623	0.00352712	0.00357173	0.00357423	0.00375548	0.00381266	0.00387647	0.00390396	0.00395009
Meta Odds	1.45816281	1.60475149	1.4869906	0.39039884	0.68581238	1.81228752	1.76520819	1.92823675	0.69198318	0.63373233	0.6194692	1.52456935	0.55470559	1.6268167	1.31935745	1.72457302	2.2848273	oo cn cd 3	1.45390139	0.60379164	1.73409156	2.80749677	0.67517857	3.01226743
MIBS P	0.89700987	0.47637974	0.01221697	0.03143414	0.15867567	0.01089829	0.00088215	0.06617482	1869Τ800Ό	0.06231333	0.72870567	0.02817001	0.46472493	CD ff) O o 6	0.0046256	0.04659244	0.53071016	0.11287341	0.83590345	0.23760335	0.04098616	0.06567196	0.06278053	0.11955976
MIBS Odds	1.035878616	1.267402965	2.270349904	0.252264495	0.641773703	2.215631346	5.059080213	2.076872691	0.46651283	0.489338494	0.862175398	2.428288153	1.552093052	2.925008861	1.942062547	2.201374994	1.526652324	1.676816197	1.062141736	2.057353645	2.189801618	cn oo cn oq CN	0.527501004	2.903606511
HIGS P	0.00076293	0.01159083	0.16726864	0.05303457	0.01733639	0.00754993	0.04966726	0.02996296	0.00236794	0.33851924	0.00121281	0.10163662	0.00020324	0.64770879	0.06991452	0.06629775	0.00148629	0.00106384	0.00167956	9.24E-05	0.01337494	0.01728117	0.11030964	0.17190288
HIGS Odds	1.79832413	1.70995826	1.27530638	0.47588685	0.68112858	2.44655616	1.6337126	2.06780589	0.6194716	0.83677802	0.52404025	1.35815008	0.37564254	1.10418786	1.25792622	1.60308204	6.6280982	1.75040285	1.74401131	0.46217996	1.98104948	8.87599881	0.75961836	2.27441112
HGDSP	0.30060169	0.09135101	0.06881669	0.2386029	0.2419302	0.64066747	0.73780601	0.31028198	0.19768884	0.00030665	0.63607216	0.08700505	0.52206122	0.00371434	0.41697392	0.18971454	0.13929326	ff) 3 ό	0.30420932	0.56966629	0.73874752	OT cn CN 0	0.05772595	0.03167379
HGDS Odds	1.28015545	1.73311846	1.58554575	0.28435755	0.73260276	0.82693415	1.13288097	1.56157271	1.43776518	0.24492626	0.84350808	1.57425902	0.79408653	2.72734178	1.15706404	1.62279091	1.71885877	δ cn oo oo oo ci	1.28401592	1.30160689	1.12742146	1.88372078	0.57535324	4.6856564
Gene	PECAM1	TGFBR2	IGF1R	IGSF2	PLXNC1	API5	PTPRM	PDGFRB	PDGFRB	PTPRD		FCRLA	STK17A	PTPRK	IL1RAPL2	PPP3CC		3	PECAM1	PTPRK	YWHAH	cn	EL0VL6	Cllorf74
Region	intron	intron	intron	intron	intron	intron	intron	intron	coding-synonymous	intron		intron	intron	intron	intron	intron		intron	locus-region	intron	intron	mrna-utr	mrna-utr	intron
	59755697	30696707	97101441	117380273	93164318	43299463	8163669	149491985	149479865	9004274	59022044	159948285	43608739	128405416	104831589	22441022	46228570	o	59753732	128870789	30673847	6090408	111190938	36602169
Chrom		cn	Lf)		rsl		oo	LD	in	σ>	σ		Γ*	CD	M CN	co	cn	oo		CD	?N	CD
SNP	rsl σ oo co	o	rsl007212	nj CN (/) 1—	Lf) rsl m 00 cn	O cn i) (/)	Lf) OO oo o oo (/)	co cn 1—	Lf) cn co σι	cn (D cn to tn	M (D o o (/)	co cn O '(Λ 1—	rs4724231	σ CD σ (/1	cn o	rsl7671456	3 cn 00 ’w)	o σ σ ίί (/1	CN OO co o Lf) o (/)	CO 2 (/) 1—	cD cn cn σ cn	W S cn (/1	δ oo oo σ CD c/ι	rs4756331

275

WO 2011/131774

PCT/EP2011/056471

Table 3

Meta P	0.00397005	0.00404405	0.00405109	0.00408808	0.00416496	0.00424479	0.00426573	0.00430369	0.00431797	0.0043842	0.00443233	0.00449866	0.00451876	0.00454599	0.00454803	0.00459501	0.00461622	0.00478853	0.00486913	0.00498422	0.00502749	0.00505693	0.0050709	0.00510485
Meta Odds	0.6752583	1.48141208	0.64097952	0.667058	0.6846441	0.68252708	0.70643279	0.64956179	0.25951327	0.66328443	0.61948187	0.67561604	0.69866146	0.70474573	1.49931704	1.65541438	0.71375152	1.58639988	1.52993899	0.69945436	0.52503672	1.46058131	1.90168302	1.78016031
MIBS P	0.59634724	0.04428658	0.00954005	0.98022829	0.11700827	0.24306781	0.61888292	0.81093925	< z	0.34602151	0.16989179	0.01979918	0.64305507	0.22869821	0.35974288	0.29093345	0.05711767	0.04913566	0.22555031	0.4048416	0.10282208	0.06533309	0.71300002	0.00152376
MIBS Odds	0.821815393	1.914602607	0.404212531	0.991516881	0.584849703	0.674616309	0.86397335	0.907922766	18864431544	0.712027543	0.507172313	0.38639699	0.869651538	0.730665214	1.33256674	1.587743147	0.598391802	2.103285337	1.546743596	0.764492866	0.43135505	1.714354514	1.178560299	4.20106486
HIGS P	0.01168965	0.00287257	99S9S6S0O	0.00330048	0.03075735	0.08236304	0.00136003	0.00269427	0.00578488	0.0476095	0.08520158	0.06356768	0.00079136	0.03329755	0.01026196	0.0722436	0.01175816	0.06567563	0.00291577	0.00126669	0.01809374	0.67991022	0.01446908	0.02125369
HIGS Odds	0.65374546	1.72048152	0.6887796	0.58684061	0.69047971	0.73904041	0.60830628	co co LT) LD m 6	0.23730079	0.69044701	0.7124517	0.73454025	0.58209238	0.70525773	(D CM LD CO LD (D	1.54643399	0.6804459	o	1.8778521	0.59088718	0.49768788	1.08058008	2.67813862	2.03966167
HGDSP	0.15886236	0.67014566	0.56389734	0.22630081	0.24049237	0.03485524	0.75903463	0.38262508	0.40453998	0.05667066	0.02080519	0.24743993	0.97027764	0.14595214	0.26558516	0.04617801	0.94437916	0.22563757	0.74357188	0.94283005	0.58881604	0.00141594	0.05712124	0.76800828
HGDS Odds	0.65812083	0.89142053	0.81583787	0.6992695	0.73586214	0.57178709	0.92267206	0.77336148	0.39268627	0.57505168	0.37152482	0.6976664	0.98980954	0.67697442	1.34410531	1.91645477	0.98153804	1.39906967	1.0920234	1.01897585	0.75555493	2.29698009	1.97297758	0.90243854
Gene	σι (D Q	YWHAH	O'	MR1		STK17B	PTPRM	PTGER3		C6orf21	BAT3	GAB2	TNFRSF1B	CMTM6	PRKCB1	PPARA	PDGFRB	g	TNFRSF19	IL2RA	PDGFRB		MADD	TNFRSF21
Region	intron	intron	intron	intron		intron	intron	intron	intron	locus-region	intron	intron	intron	intron	intron	intron	intron	intron	locus-region	intron	intron		coding-nonsynonymous	intron
	9801678	30676468	129641321	179285422	33715214	196736037	7786393	71179181	185591486	31786709	31723146	77703107	12155393	32514492	24036462	44947835	149484351	35198213	23148712	6103259	149498698	20926259	47263204	47336871
Chrom	rsl		o			cs	oo			LD	LD			cn	(D	Csl Csl	LD		cn	o	LD	CM		LD
SNP	rslO77212O	§ oo er	CM δ o ο co	(D (D δ (/) 1—	rs831603	CM O σι ΙΛΊ (/)	in CM oo co LD (/)	5) (/) 1—	(D co CT) σι tn	oo CM o OO (/)	cn LD w CM (/)	LT) cn 1—	oo oo oo (D σ> tn	δ cn (D CM (/)	Ch CO cn oo CM CM (/)	in cn m CM cn 1—	rsl075846	cn LD cn OO O (/1	co m σ) T·)	co δ CM (/) 1—	rsl7110948	δ oo δ ι_	o δ co	O m cn o 00 o (/) 1—

276

WO 2011/131774

PCT/EP2011/056471

Table 3

Meta P	0.00515029	0.00532612	0.00542323	0.00551016	0.00555203	0.0055734	0.0056319	0.00564909	0.00566318	0.00570624	0.00571641	0.00577494	0.00587133	0.00590934	0.00591907	0.00597573	0.0060638	0.00615988	0.00618391	0.00635965	0.00638771	0.00640015	0.00640311	0.0064531
Meta Odds	0.69155684	0.67275763	0.67117457	3.11823429	1.61823347	1.43993702	0.71192776	0.4062491	1.68198515	0.65739732	0.65817696	0.48971626	1.44393491	0.6819244	1.68896622	2.72399091	0.6735551	0.70198049	0.41696109	1.45208431	1.42512534	0.4765705	0.68182883	0.56756344
MIBS P	0.4959151	0.6115842	0.80696993	0.20551442	0.25585508	0.03331489	0.003037	0.08455622	0.02350067	0.10127566	0.65037355	0.64705164	0.1905506	0.30795068	0.14918366	0.50111889	0.25365564	0.18017542	0.08455622	0.90369822	0.69107942	0.06951693	Lf) o CD Lf) ό	0.40088926
MIBS Odds	0.792678685	0.830657396	1.091040447	0.180040381	1.426821775	2.218014617	0.385514916	0.417903186	1.857069082	0.549314197	0.838342811	0.753842335	1.525981289	0.718705374	1.861727809	2.007269628	0.695807839	0.688406679	0.417903186	1.039486719	0.880141582	0.138854042	0.791056985	0.66791201
HIGS P	0.00106201	0.00435674	0.0026252	0.07772938	0.30851561	0.26208827	0.06781404	< z	< z	0.03014415	0.00682232	0.00736724	0.0342318	0.00517256	0.01548032	0.05552253	0.0286662	0.01422135	z	0.0036724	0.00646771	0.00578686	0.00271653	0.00181195
HIGS Odds	0.58503629	0.61156718	0.58827213	3.27810424	1.4130263	1.21425194	0.74977347	0.76414481	0.47137687	rn ru (D (D	0.58708357	0.43950595	1.46992979	0.60948044	1.85274565	3.78156695	0.66315301	0.64120998	1.91932441	1.73502557	1.59274474	0.42665893	0.59082396	0.43117643
HGDSP	0.82242424	0.56253571	0.3038615	0.00447504	0.0134585	0.03214425	0.66494004	0.03035231	0.09589358	0.39230788	0.31748959	0.35898709	0.22045301	0.78923423	0.53864183	0.05177127	0.22702226	0.4815192	0.03348373	0.28540035	0.1077863	0.69582292	0.79976593	0.92304559
HGDS Odds	1.06794408	0.81807545	0.70455921	4.89460691	1.92239964	1.67417263	0.89887749	0.39821095	1.53893299	0.76500869	0.74220682	0.49460614	1.35296357	0.92003691	1.26643088	2.49603643	0.68171151	CSl (D m s ci	0.41633694	1.30656633	1.50756038	1.30221156	0.92951872	1.04395
Gene	MAPK10	MAPK10	CXCL9	SYNE2	cc H	IGF1R	O'	SYNE2		PTPRG	PTGER3	PTPRN2	1— (X	CMTM8	CXCL9	PTPRN2	AIRE	IL2RA	SYNE2	AGXT2	Ξ	m _________1	1— az	BCL2L1
Region	locus-region	intron	locus-region	coding-nonsynonymous	intron	intron	intron	coding-nonsynonymous		intron	intron	intron	intron	intron	locus-region	intron	coding-synonymous	intron	coding-nonsynonymous	intron	intron	locus-region	intron	intron
ci	87156570	87183196	77140838	63674348	12795499	97091849	129716363	63566502	110974792	62059196	ω	157770740	40312545	32288680	77139917	157167781	44532705	6128705	63561448	35063668	139993100	131422350	40173215	29762606
Chrom		•=4·			co CSj	LT	o		3	m			o	m				o	3	U-)	LT)	LCl	o CSj	o CSj
SNP	(D LT) Csi (/)	rsi	o ω σι (D oo CSl σι	oo co co ^) 1—	ID O CO CSJ (/)	S (D (D	s oo iD (/)	rs4027402	rslO789841	to m oo	ω ο D D co	2 ω 00 cn 1—	rsl984399	CSl	ω σι (D oo CM (/)	co rsi fsj (/) 1—	rs878081	oo στ co	CD O στ co	O co rsi fsj cn (Λ 1—	O στ στ (D Lf) tn	o CD CD (/)	Lf) OO CD O cD (/)	Lf) 00 o cD O CD (/) 1—

277

WO 2011/131774

PCT/EP2011/056471

Table 3

Meta P	0.00645468	0.00660832	0.00673216	0.00674726	0.00676621	0.00677526	0.00680458	0.00686438	0.00687617	0.00693366	0.00700235	0.00702961	0.00705888	0.00708699	0.00714929	0.00723028	0.00723465	0.00727028	0.00727045	0.00729683	0.00733444	0.00737309	0.00737979	0.00738553
Meta Odds	1.88703405	1.61216431	1.40916934	0.69977491	0.50898606	1.55132811	0.70395066	0.71699591	0.67800361	1.96037745	1.40092131	0.54867028	0.62184082	1.44173233	0.60684251	0.72623812	0.69479558	1.519783	1.56393114	1.4453417	0.7198681	1.47070868	1.53200877	0.72051256
MIBS P	0.48894885	0.78546353	0.95267953	0.22388372	0.13478287	0.00978668	0.80457051	0.01536078	0.02237032	0.1478398	0.07377876	0.48307066	0.13892818	0.19126356	0.74635877	0.09010336	0.06534918	0.04096021	0.16022376	0.28599342	0.01389573	0.04563816	0.11349463	0.01389573
MIBS Odds	1.391028202	1.101451332	1.016006939	0.698087802	0.374723896	2.669520125	0.931914458	0.448765762	0.443734676	2.21810303	1.672388773	0.56080892	0.501587784	1.534801231	0.85737766	0.653199774	0.531576091	1.933369668	1.982803974	1.400276986	0.498166411	cn O CM	1.73278306	0.498166411
HIGS P	0.16126432	0.0259514	0.00171067	0.0696807	0.00244836	0.39124357	0.04488799	0.03083353	0.03157349	0.05272256	0.20262375	0.01079712	0.0255244	0.21046792	0.04018572	0.00878969	0.09192002	0.27377029	0.09827821	0.07395592	0.05884827	0.12468672	0.05186795	0.05919215
HIGS Odds	1.57506212	1.75887237	1.75467319	0.71324157	0.39743275	1.2178954	0.70944458	0.72059793	0.67420508	1.95909625	1.23185694	0.51747943	0.60486059	1.26424017	0.64133422	CD LT) CM LD CD 6	0.74897192	1.27375763	1.40551155	1.41197006	0.73759216	1.33588972	1.54280229	0.73861498
HGDSP	0.00528618	0.04751127	0.37520045	0.10717015	0.42862493	0.07707822	0.02160896	0.91163481	0.84162285	0.2162097	0.04729491	0.47143938	0.4352407	0.02369938	0.01629732	0.95884972	0.1815313	0.0746808	0.06984944	0.08604038	0.7111396	0.13666372	0.28521545	0.7111396
HGDS Odds	3.72708636	1.94653493	1.23734492	0.67901527	1.58188687	1.65941384	0.52852523	0.97020126	0.94083493	1.79243904	1.68171221	0.68842184	0.7565952	1.74983449	0.26356574	1.01249362	0.67892026	1.70927667	1.88131724	1.5322374	0.91036251	1.4835256	1.37913032	0.91036251
Gene	2 H	PKIG	PECAM1	PRKCB1	PTPRN2	IQGAP2	SIRPA	ITGB6	O'	PDCD1LG2	SIRPA	1— cn	GATA3	TGFBR2	PTPRO	c|	_l CD	TGFBR2	CNTFR	PROC	CD S	FCRLA	STK17A	CD226
Region	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	mrna-utr	intron	intron	intron	mrna-utr	intron	intron	intron	intron	coding-nonsynonymous	coding-nonsynonymous	intron
	48086525	42664524	59760703	24039431	157569741	76029967	1865290	160693708	129669308	5508260	1857920	40208063	8156604	30697222	15399298	45903540	12143345	30706286	34551160	127902158	65710412	159948404	43630805	65706201
Chrom		o ex	£	CD		un	o CM	CM	o	σι	o CM	o CM	o	cn	CM	CM	CM	cn	σ	CM	oo			co
SNP	CD σι 00 m ω	o	cn OO o o CM CH	CM '(Λ S—	rs2335478	δ 8	o oo CM oo CO CH	co CM δ '(Λ S—	oo m O σί	o o	oo o σ CD CM CM cn	δ LD s 1—	o δ m o cn	o σ CD cn cn	rsl2814009	CM σ LT) LT) cn 1—	rsl797647	Μ co o cn cn	rsl0972149	cn cn σ σ CD o CM cn 1—	cn CD CD σ σί	cn O cD ii cn	rsl044141	rsl007822

278

WO 2011/131774

PCT/EP2011/056471

Table 3

Meta P	0.00749125	0.00753766	0.00761801	0.00770852	0.00774675	0.00782735	0.00786753	0.00791673	0.00791696	0.0079501	0.00796339	0.00801759	0.00802275	0.00802282	0.00812332	0.00847391	0.00851961	0.0085282	666SS800O	0.00856073	0.00860527	668800Ό	0.00891021	0.00891595
Meta Odds	0.70892031	1.61122769	0.7008452	0.68903243	1.75337264	0.70125031	1.45987018	1.45770814	0.71937813	0.64965334	0.66611984	1.42736818	1.81521342	1.62365628	1.57886187	1.46685181	0.16253264	1.91249249	0.72659446	1.68164239	1.54643136	0.63743958	0.57929283	1.50351852
MIBS P	0.03069494	0.50367932	0.1778523	0.38886309	0.78346793	0.76653341	0.11273327	0.86077528	0.66882685	0.16118037	0.25039759	0.18832877	0.2895987	0.00673784	96699170’0	0.30009436	0.44414345	0.32267559	0.09390401	0.46740879	3.23E-05	0.04208716	0.40088926	0.0636608
MIBS Odds	0.494195549	1.397902115	0.668067207	0.756806298	1.154819688	0.916733777	1.653502779	0.945514666	0.889299251	0.581977508	0.678411195	1.533849353	1.665236661	2.030897722	2.048397433	1.533403149	4.488678953	1.53726206	0.631269558	0.743468565	3.675177597	0.626627758	0.66791201	2.887094074
HIGS P	0.05480184	0.00235261	0.04220739	0.0150168	0.11260985	0.02521038	0.07614029	0.00484349	0.01518388	0.12689838	0.12088012	0.00863162	0.0045594	<	0.10781154	0.05844084	0.00194626	<	0.05011435	0.13376119	0.06357989	<	0.00238366	0.28448998
HIGS Odds	0.72312756	2.06334949	0.69538709	0.63732275	1.55843339	0.67581905	1.4139189	1.76018633	0.6649517	0.73801084	0.74534892	1.57921594	2.90323676	4.48E-73	1.47738548	1.44027852	0.10166663		0.73876461	1.56530554	1.56368161	1.20E+25	0.44238887	1.23815585
HGDSP	0.48533216	0.78285734	0.2635782	0.35472586	0.00898077	0.07510676	0.20650687	0.17774415	0.18078977	0.03847928	0.01940391	0.8648604	0.48092282	0.28991073	0.28432538	0.12938444	0.99976301	0.0119868	0.41988177	0.00050792	0.08521285	0.09885744	0.80671459	0.02334544
HGDS Odds	0.83961089	1.09221296	0.74115317	0.76945122	2.89131579	0.59646363	1.41619634	1.41575487	0.71790728	0.42720319	0.38601795	1.04828765	1.27572604	1.31079147	1.43123546	1.49052622	2.09 E-10	2.12093972	0.7970233	3.323853	0.5616856	0.65149321	1.11886253	1.87725168
Gene	2	PTPRN	CD160	5 CD	PPARGC1B		ITGB2	AGXT2	O'		MAP2K4		NFATC2	PPP2R1B	CLEC2B	JAK1		2	CMTM8	CBLB	KLRK1	Q	BCL2L1	IL5RA
Region	intron	intron	intron	intron	coding-nonsynonymous	intron	intron	intron	intron		intron	intron	intron	intron	intron	intron	coding-nonsynonymous	intron	intron	intron	intron	intron	intron	intron
	111131016	219865662	144408051	31705732	149192436	56961899	45148159	35037762	129749982		11947505	46047369	49455556	o	9899947	65079997	79379439	112282428	32279107	107031592	10423163	162580738	29743569	3108791
Chrom		Csl		ID	in	3		LO	o	fN		Csl	o		csl		Lf)	LD	CD	CD	£	CH	o CSj	CD
SNP	LD σι σ> LD co	oo	LD CO fsj Csl (/)	O AJ (N (/) 1—	rs7732671	σι LD cd oo	cd co oo oo csl (/)	CD CD (/) 1—	3 ω	O cn o cd fs| (/1	LD T·)	O ?) fsj (/) 1—	CD oo o LD (/)	rsl7113227	O LD Lf) (Y) cd oo T·)	fsj o CD (/) 1—	rsl7875513	oo LD O σ tn	oo oo Si (/)	o oo LD 00 ^) 1—	LD CD LD ω	O σ oo oo LD Csl (/1	σ CD oo LD o LD (/)	CD o σ 3 (Λ 1—

279

WO 2011/131774

PCT/EP2011/056471

Table 3

Meta P	0.00894574	0.00903024	0.00913438	0.00914737	0.00915385	0.00917152	0.00917463	0.00918559	0.00918659	0.00921881	0.0092717	0.00929059	0.00940624	0.00948749	0.00956242	0.00963046	0.00968206	0.00969018	0.00980005	0.00980031	0.00987629	0.0098777	0.00989768	0.00994335
Meta Odds	1.60794968	1.4624003	0.596453	1.55574268	0.67793693	2.00404703	2.13900059	0.43929499	1.39071444	1.83253888	0.60917368	1.77125565	1.3955462	0.71197963	1.34643121	1.62007531	0.45633087	0.7270181	1.45910911	1.39945812	1.42266906	0.60172257	1.43572943	1.52907649
MIBS P	0.35982347	0.04062873	0.16566189	0.16429715	0.29309131	0.8404433	0.266516	0.02656012	0.53897147	0.71300002	0.03992744	0.02145048	0.03368719	0.08975996	0.06254176	0.00343425	0.00092772	0.01743008	0.07587968	0.16079534	0.49790003	0.20360196	0.04179488	0.28954961
MIBS Odds	0.590279616	1.982043892	0.674243811	1.614843189	0.714667913	0.850565336	2.698708717	0.346839408	0.812838175	σ S cd 00	0.165726534	2.795477626	1.756625912	0.591937798	1.667940453	2.171635923	0.283691506	0.451737257	1.968171333	oo CD LD σ CD LD	1.235721111	0.49832587	1.927931615	1.336018859
HIGS P	0.02398456	0.05457562	§	0.00133522	0.01231339	0.00857334	0.15450723	< z	0.01187583	0.01510082	0.00445051	0.06042245	0.03416572	0.00404606	0.0529861	< z	< z	0.04098183	0.04726518	0.06462528	0.01323086	0.01062906	0.02966885	0.22898274
HIGS Odds	1.72345433	1.46959364	1.69161859	2.22530992	0.58465681	3.03190369	1.86248097	0.20622181	1.50742576	2.65901484	0.54068963	1.83954612	1.47150955	0.61087182	1.32095634		0.32944623	0.73334585	1.44246121	1.37699658	1.59504212	0.52789908	1.49159144	1.53079545
HGDSP	0.037121	0.54440371	0.02212076	0.63269212	0.49284778	0.14893786	0.05341758	0.12915023	0.08136811	0.10869127	0.4018486	0.71638395	0.87944921	0.51028325	0.53590471	0.45485149	0.93034401	0.91163481	0.4864228	co o co σ ό	0.35953996	0.82318503	0.93977544	0.03335376
HGDS Odds	1.92827739	1.18080511	0.53117149	0.86147211	0.82924496	1.7333281	2.32356443	0.52790505	1.54569338	1.81113639	1.46306145	1.15699539	1.03811743	1.19374349	1.1777916	1.21639487	1.04488097	0.97020126	1.23920621	1.35050667	1.26538151	0.91594261	1.0223608	1.71683397
Gene			< H	BAG1	SLAMF7	TEC	IL1RAP		BLM	MADD	1— CC	CXCL9	FKBP8		CMTM8	SNF1LK2	CUL2	ITGB6	z	I— CC	PTPRD	PBX1	YWHAH	δ H
Region	intron	coding-nonsynonymous	intron	intron	intron	intron	intron		intron	intron	intron	mrna-utr	intron	intron	intron	intron	mrna-utr	intron	intron	intron	intron	intron	intron	intron
Si	22251427	51948891	32910798	33250632	158976781	47893743	191740949	o	89156736	47268621	40713729	77143022	18513844	111130464	32292718	111035817	35339091	160695167	57030794	40278187	8991075	162803852	30678313	12801881
Chrom	(SI (Sj	p	CD	cn			co		LD	p	o (Sj		2		cn	p	o	CSI	oo	o (Sj	σ		(SI (Sj	cn (Sj
SNP	s σι m co l—	(SI σι oo LT (£) (/) s_	rs241430	O cn 1—	cD CD (7) (SI (SJ cn C—	o σ cn σ oo (£) co	rs9817149	3 LD cn cn 1—	(Y) CT) 00 CO ω C—	oo cn (/1	oo (SJ o σ cn	cn cn co cn cn 1—	CD CD in 00 o (/) C—	o oo CD (/1	oo O 00 cn co	co LD (SJ LD 00 cn 1—	rsll31510	oo o σί o (/1	rsl0104302	cn cn co 1—	rslO977434	o	OO OO cn LO oo (SJ co	rs5743740

280

WO 2011/131774

PCT/EP2011/056471

2019226219 06 Sep 2019 _OJ _Q

H

281

WO 2011/131774

PCT/EP2011/056471

Table 4

Meta P

1.81ΕΌ7

1.08E-06

5.86Ε-06

1.04E-05

1.O5E-O5

1.10E-05

1.64E-05

0.00010608

0.00012352

0.00012428

0.00012879

0.00012997

0.00013186

0.00015861

0.00018212

0.00027521

0.00032172

0.00034725

0.00040366

0.00044857

0.00058411

0.00058673

0.00066496

04

LO

rT\

ps.

LD

p-s.

LO

p^

oo

y_|

co

P'S

ΠΧ

σι

P'S

co

(D

iT

y_|

·©

04

γΎ*

ld

04

LD

o

oo

04

^*1

p*s

oo

oo

LD

p^

oo

co

LD

(D

LO

y—|

•c

o

LO

CO

y—

iTs

LD

LD

LD

σ>

LD

04

σ

co

y-

CO

Q

iTs

ο

co

iTs

1 p

o

CO

co

04

04

ld

ps^

p*s.

p's.

CO

co

p's.

i n

p*s.

o

co

CO

1 0

1 0

σ>

p. 1

^s 1

LD

1 0

p's.

O

ps^

CO

00

1 p

σ

σ

LD

o

O

(0

1 0

LO

o

o

1 0

σ>

σι

co

ps^

1 0

I p

σ

co

LD

i r\

co

y—1

i p

co

p*%*

0*1

σ

o

00

0*1

p's.

y—|

σ

p's,

ο

y—|

00

p*s

σ

Σ

cxl 6

ό

ό

LO O

CO ό

b

04 b

rd

b

LO b

b

rf

b

04

LO b

oq

LD b

LD b

LO) b

b

LD b

in

r H

y_|

04

fp

r rt

r fk

CO

r rk

OO

fSs.

co

pss

σ

co

y_!

r n

π

LD

ω

rsj

o

ω

OO

CO

CO co

00

y

93 LD

5

s

LO

σ co

σ co

CO

o

ΙΛ

LO

o

CO

y-

i rx

p*s.

LO

04

y-

co

1 k .

LO

LD

oo

co

y-

oo

oo

CO

ps

CO

y—|

t p

04

04

oo

oo

LD

o

(D

LO

o

P's.

o

LD

co

ps,

o

CO

LO

o

LD

cv”1

y—

y—

LD

P*s,

σ

o

iX'.

p*^.

oo

p*s.

o

o

04

o

o

O

CO

co

ps^

04

σι

p*%.

o

o

1 fk

0*1

I 1

oo

y—|

I 1

y—|

CO

(o

y—|

y—|

p*s

1 o

6

6

ό

6

6

6

b

b

b

ό

ό

b

b

b

ό

b

b

ό

ό

b

b

ό

CXI

σι

co

LO

σ

oo

co

co

04

LT)

OO

ps.

X

y-

1 P

p^

oo

(“s

LO

IT x

o

LO

04

04

a

cxl

CX

rxi

fXX

Ps

p's.

ps^

co

o

LO

p*^

CO

iT*

oo

LD

ίΎ*

y—

oo

o

oo

oo

Ps

LO

CO

o

04

o

10

LD

ίΎ^

o

LO

LD

10

LD

co

04

LD

ω

σι

O

co

| *1

LD

σ

pS,

co

p's.

σ

co

01

I p

00

σ

p. 1

p*

LO

co

i r\

O

i n

o

p*s.

( p

P's.

σ

1 IX

o*|

( p

o

i rk

00

O

p*

p's.

co

y—|

σι

p·*,

σ

σ

co

y—|

1 1

σ

σ

oo

σ

^*1

P's,

i rk

t pi

LO

y-

oo

04

LD

o

oo

f”yX

ΓΌ

co

LO

LD

O

p's

LD

σι

5—1

co

CO

o

co

oo

oo

LO

oo

y—|

(D

Ps

LO

LD

Ps

oo

Ps

b

5-1

ό

ό

ό

b

o

o

,-1

cd

b

b

b

l_ri

00

04

b

b

b

b

b

b

b

ω σι

LO

pj

oo

CN

04

oo

1 o

LO

(O

LD

rd

1 o

oo

LO O

ο LO

ω ο

O

o

0742

00 o

3E-0

o

1771

LO)

o

S o

co o

3191

< z

5367

1955

2824

LD oo

8436

0495

1627

2787

LO

ο

o

o

LD

y—|

o

oo

o

ο

a

o

o

o

a

o

y_^

ο

y_^

o

σϊ

LO

o

o

cd

ο

o

o

o

o

o

o

6

ό

b

b

b

b

b

b

ό

b

b

b

ό

b

b

ό

CO

γΤι

m

rT\

rT\

p-s.

co

y_|

rT\

nx

LD

oo

LD

CO

ro

P'S

CO

i n

04

LD

^sl

y—I

co

CO

1 P

co

iT*

i^'l

04

co

04

y—|

P's,

oo

oo

σ

iTs

ps

LD

CO

CXI

y—

y—

10

y—

X'X

oo

LO

y—

iT*

LO

oo

LO

LD

LD

iT*

LD

iTs

ίΎ*

CD

co

(D

t O

(r\

04

04

p*s.

LO

p*s.

04

04

( o

04

co

LJ

OO

00

p*s.

co

O,|

1 0

y—|

p*s.

i n

1 0

10

10

p's.

CO

LD

p*s

LD

LO

P*s,

σι

co

^s 1

1 0

CD

p·*,

co

oo

1 p

co

o

σ

1 0

O

oo

CO

σ

Ps

σ

co

(J

co

11 '

σ>

00

co

p*S,

O

LD

p*^

σ

1 0

i n

σ

p's.

o

σ

04

LD

1 p

CXI

rxi

LD

Q

co

y—|

p*.

σι

04

y—|

oo

LD

LD

LO

LO

LO

T

6

04

ό

ό

ό

b

b

Ή

04

b

b

b

ή

b

04

b

ή

b

b

b

b

b

in

r Η

y_|

y_|

oo

co

y_|

rT\

oo

04

co

LO

04

r n

LO

r n

P4

r rk

p's.

CO

y_|

co

σι

LO

p. 1

a

o

CO

CO

O· 1

σ

1 p

CO

1 p

^X'l

CO

^S |

o

σι

00

oo

CO

00

0*1

y—|

CO

y—|

O

co

co

σ

( p

σ

^*1

o

co

OO

LO

o

p^s

σι

LO

P's

LD

1 p

P's,

co

P's.

1 p

04

LD

co

co

04

P's.

co

Q

04

y—|

co

co

iTs

CO

CO

LD

04

o

σ>

04

y—I

oo

oo

rr

LD

LO

Ο

o

oo

o

LD

LO

LO

o

oo

Ps

LD

CXI

LO

o

Ps

σ

iT*

LD

iX1.

y—

ο

o

1 P

O

10

p*s.

iT^

LD

O

o

10

o

o

LO

r*x

p*s.

04

o

T

ο

ld

00

ld

o

1 1

pS.

y—|

O

o

o

o

o

o

y—|

ό

6

ό

ό

ό

b

b

b

b

b

b

ό

b

b

ό

b

b

b

b

ό

b

b

b

OT

f»S

fS,|

oo

px.

p's

PM

LO

oo

p-s.

04

oo

p-s.

rrs

CO

y_|

rTk

LD

LD

*□

y—|

Ο

04

iTs

X

LD

iTs

LD

oo

04

LD

LD

LO

y—|

P's,

fX”1

σ>

iTs

o

y—|

*□

CXI

p's.

LO

o

p^

σ>

co

y—

co

CO

rr

y—

y—

LO

LO

co

co

p's.

σ>

o

1 Π

oo

p^

LO

04

o

o

co

rT'i

04

p's.

p's,

co

(D

o

Ch

σι

σ>

p's.

p^

co

o

i n

σ

1 0

o

CO

LD

σ

CO

4/1

σι

σ>

co

^p

1 0

I p

co

1 0

00

σ

p's.

CO

1 0

o

σ>

1 p

Q

o

co

co

^xl

CO

σ

co

1 rk

co

1 IX

o

LD

co

i rk

rx

OO

17

ο

y—|

p**

co

LD

y—|

LD

co

co

OI

o

04

LD

LO

ps

LO

LD

J_

ό

co

ό

Ή

ό

b

b

Ή

04

04

Ή

b

b

ld

Ή

04

b

04

b

b

b

b

b

(j

(j

04

Gene

CCDC41

ΜΑΡΚ9

DOCK2

PUS7L

PDGFRB

IQ.GAP2

TNFRSF10

co cc z H

BLM

CSF1R

TNFRSF10

PTPRN2

HSP90AA

D0CK2

PTPRK

pdcdilg:

PTPRD

OSMR

MAP2K4

MAP2K4

X

Ι- α: H

MR1

(Λ

co

k

k

o

o

o

L·

L·

i=

c

c o

c

c

c

C

c

c

c

c

c

c

c

c

c

o

c

c

c

c

'Eh

c

O

c

c

0

o

ο

o

o

o

o

o

o

o

o

o

o

o

o

o

o

o

(D

o

o

o

on

c

ω

(/)

V cc

c

C

c

c

c

c

c

<Λ

c

c

c

c

c O

c

c

c

c

c

□

c

c o

c

c

oc

ζ

_c

ώ

_o

ώ

kJ

c

c

o

g

g

a

93326073

179610123

169018841

42414658

149485499

75837339

23018464

11969175

89157257

149471001

23028266

157648848

101638120

169142758

128855804

5507559

9006071

38917360

11863629

11918677

158614482

40432747

179279594

F

o

CXI

LO

LO

04

m

Lfl

oo

LD

LO

LO

oo

ps.

3·

LO

LD

σ

σ

LO

co

o

y-|

X

SNP

L2368829

00 co

L1744216

L7535213

L0072056

L0054825

L2546235

2071336

S414634

04 LO

4242389

L1773821

8005905

1863993

9482888

6476985

S440238

2278324

3826392

L2051769

1378796

6065467

3845422

υι

(/>

<s>

(/)

VI

ω

(Λ

κι

<Λ

ω

er

σι

io

(/)

σι

(Λ

(/)

(/)

σι

k_

ι_

k_

k_

k_

ι_

k_

k_

k_

282

WO 2011/131774

PCT/EP2011/056471

Table 4

Meta P	0.00072107	0.00076519	0.00078465	0.00087248	0.00091287	0.00094923	0.0009581	0.00096039	0.00102069	0.00102399	0.00111423	0.00119921	0.0012403	0.00124552	0.0012525	0.00126698	0.00131742	0.00132003	0.00132538	0.00132646	0.00133582	0.00137337	0.0014244	0.00146254
Meta Odds	1.5640073	0.55576556	0.61133786	1.80948675	1.55068941	0.61855994	0.6254446	0.57751687	1.78317553	0.5432514	0.6164075	0.63128529	1.78255866	0.66313286	1.76802039	2.44009991	0.62260685	0.46297251	0.64934295	2.30783236	0.62006744	0.6541726	0.60144396	3.86360763
MIBSP	0.03015281	0.73117837	0.30855376	0.58332157	0.35012917	0.2862399	0.65555139	0.45543429	0.25153827	0.09587792	0.81620158	0.95356449	0.25153827	0.27986195	0.04039954	0.01222177	0.4768709	0.05263728	0.13900396	0.02232057	0.16242701	0.02356977	0.53237079	0.15371941
MIBS Odds	2.310452806	1.228896815	0.672961838	0.789526971	1.389910702	0.655448359	0.837715833	1.409500379	1.655049937	0.413630679	0.915575879	0.974927042	1.655049937	0.665759136	2.654850747	4.556804728	0.734226073	0.325285615	0.507287168	3.889310136	0.567523116	0.462869036	0.712582883	4.730242662
HIGSP	0.00614501	0.00016232	0.08378924	0.00317447	0.00076293	0.01057338	0.00175443	0.00011495	0.00918138	0.00575273	0.0026252	0.00665552	0.01007464	0.00136003	0.14102305	0.01865724	0.00547374	0.02719962	0.00519201	0.05272256	0.00808487	0.00056846	0.00290621	0.49335132
HIGS Odds	1.57736681	0.45784275	0.73786157	2.02654187	1.79832413	0.64627154	0.58889226	0.44814554	1.86114844	0.54596795	0.58827213	0.64069429	1.8756407	0.60830628	1.41785272	2.59859713	0.61102113	0.53730499	0.63450801	1.95909625	0.61640983	0.56867017	0.57017516	1.64105085
HGDSP	0.3576712	0.52653486	0.00014826	0.00952767	0.43963293	0.0493405	0.20681329	0.30742213	0.09647363	0.36715836	0.08717965	0.02198811	0.10765184	0.60834621	0.01353614	0.40643508	0.13274345	0.09898674	0.33129864	0.12694632	0.23146056	0.28154335	0.27238321	0.0017172
HGDS Odds	1.27519572	0.78345665	0.25267033	2.41198802	1.21176807	0.46723502	0.64453883	0.70248295	1.71556712	0.65623976	0.5058031	0.42515295	1.69508583	0.86837964	2.19383552	1.49513964	0.60343656	0.28969938	0.76205039	2.23381373	0.67130473	1.38464673	0.67630525	6.53946184
Gene	Ι- α: H	LOC728018	PTPRD	N FATCI	PECAM1	MAP2K4	BLM	5j	PKIG	HSP90B1	CXCL9	PCGF2	ADA	PTPRM	IQGAP2	PDGFRB	BLM		TNFRSF10C	PDCD1LG2	AIRE	PDGFRB		CM < §
Region	UOJIUI	intron	intron	intron	UOJIUI	intron	intron	locus-region	intron	intron	locus-region	locus-region	coding-synonymous	intron	intron	intron	intron	intron	intron	intron	intron	intron		intron
	40849159	1820658	9004740	75263804	59755697	11935497	89113827	44920811	42667504	102861797	77140838	34143085	42686329	7786393	75931035	149486896	89115963	79821131	23018293	5508260	44534535	149477865	15575064	75912949
Chrom	o	o CM	σι	oo			lh	2	o CM	CM			o CM	oo	in	in	m	oo	oo	CT)		in		in
SNP	o m 00 O ts> l—	S oo oo ω	in o s_	to o to U3 m CM />	rs9892152	CM oo LT) rn s_	rs3815003	LO o o σι cn	o σ> o l—	cd o CM oo oo ω	o ω 2 oo CM ω	σ> o oo CM /)	ld o 1—	in CM oo co ω σι s_	CM LD CM 3 '(Λ s_	rsl0074391	CT) σ> CD ω	σι (X) o oo s_	rs4077341	LT) CM o O 'y)	rsl003854	CM cd co ω s_	o m o LD ω	rsl7652304

283

WO 2011/131774

PCT/EP2011/056471

Table 4

Meta P	0.00150463	0.00168974	0.00175191	0.00182055	0.00193313	0.00199097	0.00201972	0.00209511	0.00210867	0.00211897	0.00213939	0.00219926	0.00220974	0.00222182	0.00228823	0.00231721	0.00232585	0.0023772	0.00243689	0.00246551	0.00247535	0.00254263	0.00265991	0.00272184
Meta Odds	0.44575207	0.67624734	1.80458897	1.60293238	1.51376522	0.67448283	0.67989373	0.64778754	1.58085124	0.63897389	0.52878863	0.61461746	1.75133997	1.5813765	0.65310735	0.64845801	0.68428905	0.66556634	0.66714381	1.71358192	1.67701827	1.67503165	1.50011877	0.59559565
MIBSP	0.17217507	2.44E-05	0.69542463	0.03447804	0.2761811	0.46320706	0.0409032	0.03914729	0.74066077	0.75079711	0.87410985	0.04151254	0.09706741	0.21485661	0.33341949	0.0291322	2.44E-05	0.45979949	0.02617432	0.11569786	0.03878119	0.91761157	0.55031664	0.82584783
MIBS Odds	0.208542205	0.229441733	0.81400343	2.263995603	1.439750782	1.371604918	0.502892078	0.475557176	1.135520315	0.881837867	1.144452734	0.43635212	1.95184538	1.631801224	0.672815037	0.496605859	0.229441733	0.72936899	0.44036657	2.065974332	2.213076945	1.041064199	1.245746436	0.916673345
HIGSP	0.0034416	0.03083353	0.00193067	0.35032961	0.00171067	0.00245695	0.01175816	0.1173883	0.00484349	0.00330048	0.00020324	0.33851924	0.06345516	0.01410875	0.00560578	0.05307649	0.04098183	0.00079136	0.00452891	0.17646102	0.04833766	0.01033902	0.00167956	2.O5E-O5
HIGS Odds	0.43957631	0.72059793	2.19460251	1.20099738	1.75467319	0.6298167	0.6804459	0.75714002	1.76018633	0.58684061	0.37564254	0.83677802	1.55889951	1.62199792	0.62866877	0.68642326	0.73334585	0.58209238	0.63067265	1.38697287	1.6069948	1.89696314	1.74401131	0.38138725
HGDSP	0.54042356	0.75352212	0.0875946	0.00174144	0.54097307	0.09292498	0.54316742	0.0273209	0.11764271	0.2032679	0.74583064	2.54E-05	0.0518853	0.17083319	0.34403344	0.19973021	0.75352212	0.96835223	0.8049839	0.01047821	0.19631716	0.0363718	0.46433271	0.45765546
HGDS Odds	0.64895553	1.09178513	1.77178098	2.57357265	1.16581079	0.6311328	0.84122055	0.51129422	1.53186639	0.67279722	0.88797357	0.1428006	2.18359035	1.47588642	0.73782139	0.7036857	1.09178513	0.98849714	1.07800003	2.26291757	1.49949889	1.84921488	1.20359468	1.3106124
Gene	DOCK2	ITGB6	in	IQGAP2	PECAM1		PDGFRB	Ι- α: H	AGXT2	MR1	STK17A	PTPRD	HDAC4	g	PTPRN2	MAPK4	ITGB6	TNFRSF1B	PDGFRB	rsl < §	1— cc	C17orf85	PECAM1	PPP2R2B
Region	U0J1UI	intron	coding-nonsynonymous	intron	UOJ1UI		intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	locus-region	intron
	169394879	160693708	160384673	75942821	59760703	30570063	149484351	40237760	35037762	179285422	43608739	9004274	239852569	35207094	157177926	46494835	160695167	12155393	149478344	75924224	40354563	3664884	59753732	146166067
Chrom	in	CN	rsi	in		ω	Ln	o fsj	LT)			στ	CN	3		oo	CN		Ln	in	o rsj			in
SNP	rs9313487	OO cn δ	S in csj ΟΪ (N 'ω s_	o σι cn cn ω	rs2070783	ω 3 CM υτ	rsl075846	W CO o ID ω	rsl3173943	στ o </) s_	cn ru	rs613613	rs6742576	Ln cn co s (/) s_	rsl638006	CSI LO στ 'Ϋτ	rsl0497208	oo oo oo ω στ σι s_	rs246394	στ cn us cn cn 4/)	rsl573706	rsl7763453	03 CO o Ln o ω	rsl61042

284

WO 2011/131774

PCT/EP2011/056471

Table 4

Meta P	0.00275769	0.00276883	0.0027894	0.00281082	0.00281937	0.00285523	0.00291847	0.00297676	0.00312637	0.00312925	0.00316234	0.00326861	0.00327793	0.00333424	0.00337387	0.00337616	0.00343648	0.00343895	0.0034403	0.00346769	0.00351449	0.00356592	0.0036519	0.00365776
Meta Odds	1.5518509	0.5323338	1.605386	2.09141994	1.53297046	1.66167608	0.65732858	1.56120614	2.89090119	0.68401986	0.68483547	0.59542387	0.67856609	1.60426941	1.477545	2.2787084	0.69435573	0.67294756	0.44557584	1.52797732	2.45381211	0.66436007	0.65169287	1.99075048
MIBSP	0.04842032	0.24618281	0.13973038	0.0752997	0.74066077	0.16148837	0.05636814	0.34269455	0.00055812	0.00440838	0.00440838	0.86384871	0.25481129	0.63734029	0.25015386	0.38991522	88960Τ99Ό	0.50519681	0.00339299	0.86130551	0.03022541	0.27826946	0.05226772	0.28176322
MIBS Odds	2.459090844	0.570364102	1.701486593	2.914679958	1.135520315	2.116813201	0.467296279	1.431999362	9.982484611	0.37050971	0.37050971	1.075853393	0.642026655	1.184086117	0.629670784	1.614806551	0.856265088	0.800559925	0.089255123	0.932227215	3.329956454	0.707613566	0.357821168	1.925732512
HIGSP	0.10163662	0.03097707	0.02261696	0.02996296	0.0036724	0.01577555	0.01375692	0.01026196	0.07353594	0.05884827	0.05919215	7.72E-06	0.01733639	0.01159083	0.0038546	< z	0.00039605	0.04488799	0.02930569	0.00253158	0.00846313	0.00435674	0.00026877	0.0045594
HIGS Odds	1.35815008	0.55987429	1.63849578	2.06780589	1.73502557	1.68780469	0.64014021	1.67553526	2.59667403	0.73759216	0.73861498	0.36047838	0.68112858	1.70995826	1.61292084	c	0.57726445	oo lh σ o ό	0.47126387	1.75339747	3.71934504	0.61156718	0.52537558	2.90323676
HGDSP	0.04261883	0.07218081	0.19643664	0.22087157	0.21352732	0.22675894	0.4595754	0.20435086	0.82748284	0.40429658	0.40429658	0.35609199	0.1907413	0.0867806	0.04522154	0.00382559	0.87305095	0.01962402	0.688464	0.21707063	0.86532931	0.75710477	0.15881083	0.29803193
HGDS Odds	1.75481239	0.42542725	1.47989139	1.75835283	1.38945614	1.47283872	0.81783308	1.42703837	0.85658553	0.79877362	0.79877362	1.40187743	0.69066171	1.79111758	1.71901496	2.5624024	1.04244072	0.50163574	0.80015969	1.41934278	1.09771229	0.89211758	1.54565632	1.44353751
Gene	FCRLA	CD59	ITGA9	PDGFRB	AGXT2	FBN3	CD59	PRKCB1	1— cc	CD226	CD226	PPP2R2B	PLXNC1	TGFBR2	s	z	IL2RA	SIRPA	F13A1	TNFRSF1B	s	MAPK10		NFATC2
Region	UOJIUI	mrna-utr	intron	intron	UOJIUI	coding-nonsynonymous	mrna-utr	intron	intron	intron	intron	intron	intron	intron	mrna-utr	intron	intron	intron	intron	intron	intron	intron	intron	intron
	159948285	33686248	37642638	149491985	35063668	8109328	33681356	24036462	40786436	65710412	65706201	146189300	93164318	30696707	101317699	112282428	6119852	1865290	6098001	12156341	41221364	87183196	48007571	49455556
Chrom		3	cn	in	in	σ>	3	CD	o CN	oo	oo	in	CN	cn	CN	CD	o	o CN	cD		LC)		3	o (N
SNP	rsll05238	σ> cn CN cn O	S 3 ω	rs3733678	o oo cn </)	cd cn cD CN ω	rs704697	σ cn m oo (N (N c/i	σ> σ σι	cn CD σ cd σ 'ω	OO O O ω	nJ O CD t/ι	LH cn 00 (/)	o LH m σ σι	CD ω	CN oo (D O σ (/)	rs7072398	rs3828016	00 lh LD o cn co	rs976881	m o	δ cn 'T)	rs7130876	cn 00 nJ O (D 4/)

285

WO 2011/131774

PCT/EP2011/056471

Table 4

Meta P	0.00383111	0.00391466	0.00401273	0.00420173	0.00426387	0.00428548	0.00433721	0.00434884	0.0044037	0.00441809	0.00444665	0.00445714	0.00452342	0.00452569	0.00452998	0.00453749	0.00467196	0.00472586	0.00472636	0.00477793	0.00480705	0.00482864	0.00483857	0.00486188
Meta Odds	0.67359438	0.69192431	1.88287184	0.64720367	0.64910947	0.67483508	0.70158138	0.683401	1.69990307	5.99409961	1.9493235	0.67165266	1.46637086	0.67605094	0.39451609	0.26156534	0.69338691	0.6809586	0.66011681	0.54040786	1.72989626	0.65874323	0.69761017	0.61156058
MIBSP	0.1909502	0.467531	0.55400167	0.94369336	0.5515047	0.233687	0.02321788	0.40959324	0.42259279	0.00276237	0.23779462	0.00654404	0.05468089	0.154871	0.04714885	< z	0.02696439	0.04039748	0.18861383	0.60068371	0.00655085	0.13832885	0.030224	0.45543166
MIBS Odds	0.626696378	0.76514178	1.478295674	1.032014723	0.777886845	0.633695267	0.509902099	0.755301384	1.412033578	12.09770863	1.819176447	0.337476773	2.203360165	0.605725581	0.214111262	18643042927	0.458094524	0.569077489	0.569607579	0.732955751	3.921246215	0.57107144	0.469457936	0.669055839
HIGSP	0.03179239	0.01799934	0.11260985	0.01306354	0.00098157	0.08236304	0.00878969	0.00106201	0.0259514	z	0.00560456	0.09192002	0.02330856	0.0696807	0.05303457	0.00578488	0.00236794	0.07735733	0.00517256	0.00181195	0.07946045	0.02247829	0.05011435	0.00097469
HIGS Odds	0.69472635	0.69046153	1.55843339	0.62947384	0.54286612	0.73904041	0.65154256	0.58503629	1.75887237	0.21061583	2.88724265	0.74897192	1.48956715	0.71324157	0.47588685	0.23730079	0.6194716	0.72046124	0.60948044	0.43117643	1.59107034	0.6513769	0.73876461	0.48971131
HGDSP	0.1435302	0.12886739	0.00589543	0.06535639	0.92248422	0.03324443	0.85817157	0.74215687	0.09789911	0.37113726	0.34867961	0.26179611	0.39538637	0.08571383	0.25225893	0.42558509	0.27133701	0.2684215	0.9051644	0.81688231	0.38907767	0.35551237	0.34382198	0.86197643
HGDS Odds	0.64314341	0.65847522	3.20354454	0.55014299	1.03295124	0.55320744	1.04566366	1.10853608	1.80520247	2.35933243	1.40983092	0.71062358	1.23123613	0.64831743	0.29276092	0.40984979	1.38582698	0.7247334	0.96089791	0.895837	1.34971585	0.74922786	0.75313095	1.06335655
Gene	EL0VL6	PTPRM	PPARGC1B	LTT 1— < CD	x	STK17B	PRKCE	MAPK10	PKIG	SLAMF6	tn cc z H	BCL2L14		PRKCB1	IGSF2	IRF2	PDGFRB	PDGFRB	CMTM8	BCL2L1	IL1RAP		CMTM8	H
Region	locus-region	intron	coding-nonsynonymous	intron	U0J1UI	intron	intron	locus-region	intron	intron	intron	mrna-utr	intron	intron	intron	intron	coding-synonymous	intron	intron	intron	intron		intron	locus-region
	111189034	7805873	149192436	31773173	158512216	196736037	45903540	87156570	42664524	158738437	23106829	12143345	205870218	24039431	117380273	185591486	149479865	149476514	32288680	29762606	191844191	15576875	32279107	133477726
Chrom		oo	Lf)	LD		CM	rsi		o rd		ro	rd		LD			LT)	Lf)	co	o rd	co		co	LD
SNP	m o m m oo LD co	oo στ oo στ Ίλ	rs7732671	rd O 00 ι/i	o LD S LD (/)	O ω in σι	2 Lf) (/)	LD LT) Lf) rd (H	στ O l—	LD s_	rs7987909	rsl797647	ro co o στ l—	rsl στ LD tn s_	στ 3 rd rd ω	(D 00 (Y) στ t/ι	LTT στ l—	o στ CO LD s_	LT) LTT 3	W O (D O (D (/)	rs9831803	oo LD o s_	rs4245886	(D LTT (D

286

WO 2011/131774

PCT/EP2011/056471

Table 4

Meta P	0.00498185	0.00502758	0.00511685	0.00516092	0.00521911	0.00527658	0.00528067	0.0053456	0.00536337	0.00541026	0.00542248	0.0054606	0.00546749	0.00548652	0.00559256	0.00562835	0.00567987	0.00569168	0.00571302	0.00575959	0.00588403	0.00591764	0.00593852	0.00621838
Meta Odds	2.37904215	1.58260036	1.46701047	1.88000109	1.40224352	0.65098707	0.62441721	0.69595111	0.6838719	0.68492502	0.66113266	2.07360552	1.84994048	0.62946059	0.60311188	0.69015028	1.46627399	1.66927173	1.49145813	1.31936028	1.46480877	1.64336082	1.47683865	0.6191119
MIBSP	0.20808618	0.11254484	0.14002211	0.27972342	0.02300502	0.06324674	0.02268151	0.01211854	0.12308197	0.01518957	0.04781715	0.17898745	0.71387947	0.87097154	0.24739883	0.56782914	0.28635744	0.12694004	0.02367452	0.15015776	0.01579015	0.00436883	0.03149599	0.2796878
MIBS Odds	4.730951503	2.135278739	1.64977881	1.800676856	2.310419141	0.504992842	0.39689553	0.409810295	0.551646182	0.417295012	2.166432987	1.823670971	1.230686828	1.088478107	0.587645404	0.789227493	1.428769234	1.748933254	2.658471404	1.409589457	2.729934463	4.219859274	1.84576278	0.580423115
HIGSP	0.15450723	0.05529258	0.00863162	0.00486086	0.0529861	0.02210027	0.02243608	0.03842952	0.03075735	0.00404606	0.00026652	< z	0.02115822	0.00121281	0.05626947	0.02875229	0.01789273	0.30851561	0.00287257	0.04939986	0.16726864	0.06374432	0.1075962	0.10011032
HIGS Odds	1.86248097	1.45596316	1.57921594	2.63656846	1.32095634	0.63187513	0.60790359	0.71121514	0.69047971	0.61087182	0.48692773	0.43080195	1.95408011	0.52404025	0.65721731	0.70517477	1.54496509	1.4130263	1.72048152	1.3068943	1.27530638	1.56924172	1.37728226	0.71273483
HGDSP	0.02464441	0.12460998	0.76799091	0.42616821	0.32982957	0.59736723	0.87839576	0.63844854	0.29031682	0.38183122	0.14196536	0.01398437	0.08885017	0.77565299	0.0634589	0.08714542	0.28994099	0.03143813	0.47453164	0.18109236	0.09640159	0.52829257	0.27972083	0.01461099
HGDS Odds	2.85058652	1.79149362	1.09030672	1.32934137	1.31637632	0.84607856	0.94723133	0.88291236	0.74543407	1.28335256	0.664833	2.2184953	2.07470652	0.89952742	0.42123728	0.59305484	1.33148163	1.81654223	0.81528639	1.28882708	1.55869331	1.22252083	1.36261441	0.33689733
Gene	IL1RAP	CNTFR	PRKCE	Ι- α: Η	CMTM8	SPINK5		CD226			MAPK9	SLAMF6	F13A1		Ι- ο: H	PTPRN2	1— cc	δ H	YWHAH	IL1RAPL2	IGF1R	cD	CD28	CYLD
Region	UOJIUI	intron	intron	intron	UOJIUI	intron	intron	intron		intron	intron	intron	intron		intron	intron	intron	intron	intron	intron	intron	coding-nonsynonymous	locus-region	intron
	191740949	34556190	46047369	40380498	32292718	147471725	75342967	65696478	33715214	111130464	179612366	158723751	6118369	59022044	40363108	157343101	40856507	12795499	30676468	104690227	97101441	157253101	204278337	49385102
Chrom	co	στ	CSl	ο esj	Cf)	Lf)	o	oo			Lf)		CD	O)	o CSj		o esj	co CsJ	CSl CsJ	Cf) fsj	Lf)		CSl	cD
SNP	rs9817149	o cd CM Ίλ	O LD Lf) CSJ ω	rsl7317153	rs4572808	oo cd So fsj CsJ ω	S CSl CsJ ω	rs4094864	rs831603	δ Lf) oo LD ω	03 00 O co CD oo LD cn	rsl041067	rsl7141840	S co LD o 3 (/)	O CD LT) CD O LD (/)	rsl2667537	rsl7811425	CD rsi O co CsJ (/)	o o O r>i oo co	O 00 στ ΓΊ CD CD (Z)	δ o tn	oo CD CD OO (/)	rs3181096	στ CN o Cf) fsj (Z)

287

WO 2011/131774

PCT/EP2011/056471

Table 4

Meta P	0.00623442	0.00624054	0.00626233	0.00628683	0.00631208	0.00636386	0.00651877	0.00659895	0.00666053	0.00668182	0.00672637	0.00688493	0.00692522	0.00697574	0.00701027	0.00711592	0.00715909	0.00726788	0.00737466	0.00742465	0.00748396	0.00760094	0.00764643	0.00770211
Meta Odds	1.49849868	1.67156256	0.69490504	1.78382912	0.68786418	3.10843837	1.44792048	1.53618707	1.54750999	0.64537547	1.63851165	0.55342866	0.69784007	0.64947734	1.46103026	2.85777667	1.51025069	1.44433829	1.43409468	1.85014939	0.7104371	0.68924202	1.4161782	1.42502266
MIBSP	0.07374143	0.32068033	0.298268	0.78806174	0.47013849	0.11776871	0.44422561	0.34480767	0.18486799	0.22225372	0.78892856	0.60068371	0.01297711	0.0030658	0.74404124	0.65899547	0.48285441	0.27809817	0.24263104	0.58443051	0.50995334	0.00654404	0.3183848	0.02812813
MIBS Odds	2.311760859	0.515875154	0.648216671	1.174127844	0.789642141	3.091031331	1.351465322	1.450965731	1.797560506	0.602191129	1.127438262	0.732955751	0.391594532	0.305341161	0.886855435	0.574738926	1.277095333	1.461046463	1.464967692	1.417426141	0.787432901	0.337476773	0.690759416	2.139825301
HIGSP	0.12468672	0.02398456	0.00126669	0.00444984	0.02521038	0.01728117	0.00106384	0.04684429	0.04867542	0.12088012	0.0722436	0.00238366	0.05480184	0.24768847	0.06850014	0.05552253	0.0075062	0.0342318	0.03270155	0.01288866	0.0188805	0.11066569	0.01187583	0.02843145
HIGS Odds	1.33588972	1.72345433	0.59088718	2.34009523	0.67581905	8.87599881	1.75040285	1.51983072	1.54025474	0.74534892	1.54643399	0.44238887	0.72312756	0.76981675	1.3875101	3.78156695	1.76038942	1.46992979	1.46857224	2.23726449	0.68663689	0.76117236	1.50742576	1.45817642
HGDSP	0.07041442	0.02489912	0.63633591	0.30825037	0.1415216	0.27132607	0.76719657	0.10735731	0.17169416	0.00896293	0.01612296	0.94244112	0.54038359	0.23151259	0.00453832	0.02222804	0.40339922	0.20837745	0.24834257	0.23747814	0.24483727	0.36369491	0.03857242	0.79641874
HGDS Odds	1.64949637	2.1220002	1.13945745	1.42452019	0.64573737	1.9586438	0.92228597	1.62323973	1.46806911	0.30015344	2.32421494	0.96518672	0.85015165	0.72051209	2.25036285	3.20084147	1.27313525	1.38508533	1.34748907	1.56594405	0.73755539	0.76049374	1.7414468	1.07002722
Gene	FCRLA		IL2RA	MAPK9	CC Ll_	F13A1	D _________1	NCK1	ITGA9	MAP2K4	PPARA	BCL2L1	5	H	PTPRU	PTPRN2	PRKCE	Ι- α: H	MBL2	TEX12	PROMI	BCL2L14	BLM	CD226
Region	coding-nonsynonymous	intron	intron	intron	UOJIUI	mrna-utr	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	intron	locus-region	intron	intron	intron	coding-nonsynonymous
	159948404	22251427	6103259	179602877	56961899	6090408	27512170	138101599	37741319	11947505	44947835	29743569	111131016	129715311	29497962	157167781	46044534	40312545	54199263	111548824	15604412	12143028	89156736	65682622
Chrom		CM CM	o	LD	2	ω	oo	cn	cn		CM CM	o CM		o			CM	o CM	o	3		CM	m	oo
SNP	cn o <d LT) ω	LD ΟΊ σ» LT) ω	ω oo (D o CM ω	rs4639174	rsl7834679	ω oo o cn ω	o s δ CM ω	cn (D oo 1/)	o o CM (/)	ld *V)	LD CO m CM (/)	σ> cn oo un o (D (/)	rs7692976	ω CM oo (D (/)	cn (D CM	3 oo CM CM (/)	W 5) (/)	σι σι cn oo σ> σι	rsl838065	rsll214108	rs717176	LD ω σι 'σ!	cn cn oo cn CM CM tn	rs763361

288

WO 2011/131774

PCT/EP2011/056471

Table 4

Meta P	0.00772918	0.00779681	0.00782152	0.00787324	0.00793313	0.00804314	0.00805292	0.00808053	0.0080995	0.00812478	0.00823818	0.00825819	0.00826286	0.00828454	0.00837565	0.00838392	0.00839616	0.0084421	0.00850426	0.00851779	0.00853525	0.00867939	0.00879554	0.00883537
Meta Odds	0.36264054	0.60133443	0.69784319	0.66420876	0.67718014	0.37561345	1.29134824	0.64673151	0.62224421	0.64405121	0.70858004	3.08321144	0.70286829	1.43368631	1.55179894	0.67339544	2.85293367	0.22168005	0.53511478	2.40061042	1.68803574	0.71596244	0.49653661	1.7000779
MIBSP	0.25934214	0.09376977	0.42203158	0.93208105	0.06316575	0.25934214	0.08095319	0.7963535	0.09398897	0.10309747	0.93275275	0.34610186	0.20495758	0.59863126	0.09285948	0.29845254	0.00172115	0.1309925	0.19790608	0.88114281	0.16245636	0.53464507	0.15503289	0.20030419
MIBS Odds	0.506797492	0.275876819	0.778632189	1.038205399	0.499496867	0.506797492	1.52859881	0.886809564	0.429676157	CD (X) (X) 5- S 0	0.969463603	0.296239826	0.652163756	1.243435996	1.966917559	0.675150083	12.48444708	0.354546359	0.456298626	1.166206662	1.980703511	1.240225714	0.197387295	1.877809135
HIGSP	< z	0.00445051	0.06181018	0.00269427	0.23978875	< z	0.06991452	0.02470974	0.0255244	0.12689838	0.00034599	0.07772938	0.00245033	0.05996023	0.05186795	0.0286662	0.26149332	z	0.01809374	0.26604918	0.02747993	0.01543522	0.05155452	0.06950403
HIGS Odds	0.76414481	0.54068963	0.71271184	0.55588639	0.80092435	1.91932441	1.25792622	0.64739941	0.60486059	0.73801084	0.55127786	3.27810424	0.60057077	1.38107099	1.54280229	0.66315301	2.20757565	2.46E-161	0.49768788	1.76884429	1.84726427	0.68154856	0.55754201	1.65957717
HGDSP	0.01182678	0.49302644	0.06917241	0.52082934	0.03951804	0.01315874	0.26019742	0.09690156	0.57424039	0.05819758	0.70820629	0.00874223	0.5691142	0.05648367	0.34792227	0.2927785	0.49237438	0.01288301	0.61226492	0.00687723	0.39325823	0.05289113	0.15612895	0.16037886
HGDS Odds	0.29027382	1.39292381	0.61471861	0.82329266	0.54023628	0.31358432	1.23663197	0.49699735	0.81437984	0.45089796	1.10034772	4.93816542	1.17849809	1.66696778	1.35120379	0.70507698	1.51074004	0.07642322	0.76392252	3.69492819	1.34848656	0.59007603	0.37852792	1.67691064
Gene	SYNE2	Ι- α: Η	PRKCE	PTGER3	BCL6	NAS	IL1RAPL2	CBLB	GATA3		PRKCE	SYNE2	5	CD _j	STK17A	AIRE	F2R	VDR	PDGFRB	PTPRN2	ATRN		BLM	PTPRH
Region	coding-nonsynonymous	intron	intron	intron	UOJIUI	coding-nonsynonymous	intron	intron	mrna-utr		intron	coding-nonsynonymous	intron	coding-nonsynonymous	coding-nonsynonymous	coding-synonymous	intron	intron	intron	intron	locus-region	mrna-utr	coding-nonsynonymous	intron
	63566502	40713729	46045487	71179181	188942191	63561448	104831589	106985186	8156604	7157242	46134145	63674348	111142028	159060184	43630805	44532705	76054800	46525167	149498698	157330723	3398811	356064	89127103	60400287
Chrom		ο CM	CM			3	co CM	co	o	CM	CM						LT)	CM	U-)		o CM	ω	LD	2
SNP	8 o ω	m oo CM o σ> (/) s_	8 CO LO Ίλ	rs7541717	σζ m ω	ω CM O <d ω	CO O s_	co o oo ID 1/)	oo LO o ω	O CO LT) o co CM ω	CD CO LO CD ω	rsl2881815	rs9991904	<D σ> o (/) s_	rsl044141	rs878081	00 CM CM CM (/)	rsll574113	rsl7110948	s LT) (X) oo	CO CO CM LO LO (/)	o oo (/) s_	s CO CM 03 'ω s_	oo oo CM CM 4/)

289

WO 2011/131774

PCT/EP2011/056471

Table 4

Meta P	0.00884885	0.00891196	0.00892432	0.00895345	0.00897021	0.00899615	0.00903621	0.00919713	0.00948614	0.00954347	0.00955962	0.0095633	0.00958124	0.00958255	0.00958826	0.00972508	0.00975546	0.00976474	0.0098283	0.00991575	0.00996644
Meta Odds	1.42534666	1.50606072	1.49666589	1.41990798	1.50698683	1.57527645	1.48498599	2.14058282	1.82622304	0.70630159	1.51632475	60Ζ88069Ό	1.39187312	1.47214103	1.59146367	0.64042143	0.67509588	1.4390963	0.28068663	1.40615531	1.67286965
MIBSP	0.03098742	0.23455732	0.97346744	0.69090086	0.0477614	0.02463277	0.1051811	0.58188286	0.01904235	0.06772627	0.1439632	0.10696314	0.45071999	0.22290112	0.29047753	0.01544164	0.00971569	0.0196301	0.09134851	0.18439689	0.15422973
MIBS Odds	1.991587477	1.623563578	0.987701372	0.863159962	2.283820346	2.712132468	2.153080222	0.670047968	4.424252439	0.512380618	2.528852728	0.439096926	1.256490192	1.837816069	1.557420871	0.386478551	0.191015467	2.249557811	0.262332634	1.527641748	2.213446139
HIGSP	0.03416572	0.00291577	0.04810873	0.00646771	0.50840081	0.1563137	0.04726518	0.00148629	0.04672765	0.06606352	0.28448998	0.06356768	0.04788534	0.03825241	0.00133522	0.25507792	0.06700756	0.67991022	< z	0.01258535	0.06629775
HIGS Odds	1.47150955	1.8778521	1.51384634	1.59274474	1.14298838	1.37147549	1.44246121	6.6280982	1.92846985	0.72325427	1.23815585	0.73454025	1.39321068	1.49333138	2.22530992	0.7743799	0.71982913	oo o o oo o OO O	0.01236529	1.51539468	1.60308204
HGDSP	0.8007258	0.93879471	0.02841666	0.216763	0.00733668	0.19915925	0.32678276	0.10142812	0.57989157	0.32792438	0.01128258	0.20267608	0.11969393	0.26382119	0.75541553	0.16519214	0.37841053	0.01102149	0.05042848	0.91214827	0.21643286
HGDS Odds	1.06807784	0.97848495	1.87710308	1.39020846	2.2993276	1.58216805	1.36776903	1.85735199	1.23466277	0.78255986	2.13450415	0.65565062	1.49689483	1.34572269	0.90288507	0.59954867	0.75456541	1.98404501	0.29285052	1.03323499	1.61060959
Gene	FKBP8	TNFRSF19	MAP2K4	CD14	IQ.GAP2	ITGA9	z _j		CSF1R	DUSP2	IL5RA	GAB2	o	PTPRZ1	BAG1	Ι- α: H	o _________1		VDR	PLXNC1	rn
Region	UOJIUI	locus-region	intron	intron	UOJIUI	intron	intron		locus-region	mrna-utr	intron	intron	intron	intron	intron	intron	mrna-utr		intron	intron	intron
	18513844	23148712	11983357	139993100	75911385	37502408	57030794	46228570	149412806	96173058	3108791	77703107	113544921	121339630	33250632	40843315	205008152	20926259	46537809	93220659	22441022
Chrom	2	cn	2	in	in	cn	oo	cn	LT)	CM	cn	3	CM		σ>	o CM		CM CM	CM	CM	00
SNP	rslO854166	oo LO ι_	rs8078439	o 2 2 m CM 1/)	rsl7748322	δ o oo	rsl0104302	3 CM cn 00	rsl062069	O	cn o σ> 3 ω	rsll237451	rsl0165797	ω oo CD O CM ω	rs706121	rsl3042473	00 σ> o cn	δ oo CM (/)	δ CM OO CD	o cn oo	rsl7671456

290

Claims (87)

1. WHAT IS CLAIMED IS:

   _H 1. A method for predicting the risk of developing antibodies against Factor

   VIII (FVIII) in an individual diagnosed with Hemophilia, the method comprising the steps of:

   (a) detecting the presence of at least one single nucleotide polymorphism

   5 (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4, in a biological sample from the individual; and (b) predicting the risk of the individual of developing antibodies to FVIII.
2. 2. The method of claim 1, wherein the detection of a SNP associated with an

   0 odds ratio of less than 1 is predictive of a decreased risk of developing antibodies against FVIII and the detection of a SNP associated with an odds ratio of more than 1.0 is predictive of an increased risk of developing antibodies against FVIII.
3. 3. The method of claim 1 or 2, wherein the individual has not received therapy comprising administration of FVIII.
4. 5 4. The method of claim 1 or 2, wherein the individual has received therapy comprising administration of FVIII.

   5. The method according to any one of claims 1 to 4, wherein the individual has been diagnosed with mild Hemophilia.
5. 6. The method according to any one of claims 1 to 4, wherein the individual 20 has been diagnosed with moderate Hemophilia.
6. 7. The method according to any one of claims 1 to 4, wherein the individual has been diagnosed with severe Hemophilia.
7. 8. The method of claim 7, wherein the at least one single nucleotide polymorphism (SNP) is a SNP listed in Table 2 or a SNP listed in Table 4.

   25
8. 9. The method according to any one of claims 1 to 8, wherein the step of detecting the presence of at least one SNP comprises amplifying a nucleic acid present in the biological sample.

   291

   WO 2011/131774

   PCT/EP2011/056471
9. 10. The method of claim according to any one of claims 1 to 9 wherein the _H step of detecting the presence of at least one SNP comprises a technique selected from the group consisting of mass spectroscopy, RT-PCR, microarray hybridization, pyrosequencing, thermal cycle sequencing, capillary array sequencing, and solid phase sequencing.

   5
10. 11. The method of claim according to any one of claims 1 to 10, wherein the step of detecting the presence of at least one SNP comprises a methods selected from the group consisting of a hybridization-based method, an enzymatic-based method, a PCR-based method, a sequencing method, a ssDNA conformational method, and a DNA melting temperature assay.
11. 12. The method of claim according to any one of claims 1 to 11, wherein the

    0 step of detecting the presence of at least one SNP comprises comprises microarray hybridization.
12. 13. The method according to any one of claims 1 to 12, wherein the SNP is selected from the group consisting of rsl2368829, rsl 1744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712.
13. 14. The method according to any one of claims 1 to 13, wherein at least one

    5 detected SNP is rsl2368829.
14. 15. The method according to any one of claims 1 to 14, wherein at least one detected SNP is rsl 1744216.
15. 16. The method according to any one of claims 1 to 15, wherein at least one detected SNP is rsl863993.

    20
16. 17. The method according to any one of claims 1 to 16, wherein at least one detected SNP is rs4147385.
17. 18. The method according to any one of claims 1 to 17, wherein at least one detected SNP is rsl2546235.
18. 19. The method according to any one of claims 1 to 18, wherein at least one

    25 detected SNP is rs4242389.

    292

    WO 2011/131774

    PCT/EP2011/056471
19. 20. The method according to any one of claims 1 to 19, wherein at least one detected SNP is rsl0054825.
20. 21. The method according to any one of claims 1 to 20, wherein at least one detected SNP is rsl7535213.
21. 22. The method according to any one of claims 1 to 21, wherein at least one detected SNP is rsl0072056.
22. 23. The method according to any one of claims 1 to 22, wherein at least one detected SNP is rsl7725712.
23. 24. The method according to any one of claims 8 to 12, wherein the SNP is selected from the group consisting of rsl2368829, rs4147385, rsl 1744216, rsl863993, rsl7535213, rsl0072056, rsl0054825, rsl2546235, rs4242389, rs2071336, rs414634, rsl7725712, rsl 1773821, rs8005905, and rs9482888.
24. 25. The method of claim 24, wherein at least one detected SNP is rs 12368829.
25. 26. The method of claim 24 or 25, wherein at least one detected SNP is rs4147385.
26. 27. The method according to any one of claims 24 to 26, wherein at least one detected SNP is rsl 1744216.
27. 28. The method according to any one of claims 24 to 27, wherein at least one detected SNP is rsl863993.
28. 29. The method according to any one of claims 24 to 28, wherein at least one detected SNP is rsl7535213.
29. 30. The method according to any one of claims 24 to 29, wherein at least one detected SNP is rsl0072056.
30. 31. The method according to any one of claims 24 to 30, wherein at least one detected SNP is rsl0054825.

    293

    WO 2011/131774

    PCT/EP2011/056471

    2019226219 06 Sep 2019
31. 32. The method according to any one of claims 24 to 31, wherein at least one detected SNP is rsl2546235.
32. 33. The method according to any one of claims 24 to 32, wherein at least one detected SNP is rs4242389.

    5
33. 34. The method according to any one of claims 24 to 33, wherein at least one detected SNP is rs2071336.
34. 35. The method according to any one of claims 24 to 34, wherein at least one detected SNP is rs414634.
35. 36. The method according to any one of claims 24 to 35, wherein at least one 0 detected SNP is rs 17725712.
36. 37. The method according to any one of claims 24 to 36, wherein at least one detected SNP is rsl 1773821.
37. 38. The method according to any one of claims 24 to 37, wherein at least one detected SNP is rs8005905.

    5
38. 39. The method according to any one of claims 24 to 38, wherein at least one detected SNP is rs9482888.
39. 40. The method according to any one of claims 1 to 39, wherein the method further comprises assigning a treatment to the individual based on the predicted risk of developing antibodies against Factor VIII.

    20
40. 41. The method of claim 40, wherein the treatment comprises administration of Factor VIII.
41. 42. The method of claim 40, wherein the treatment comprises administration of a non-Factor VIII hemostatic agent.
42. 43. The method of claim 40, wherein the treatment comprises administration 25 of Factor VIII and a non-Factor VIII hemostatic agent.

    294

    WO 2011/131774

    PCT/EP2011/056471
43. 44. The method of claim 40, wherein treatment comprising administration of _H Factor VIII is assigned to an individual with a predicted decreased risk of developing antibodies against Factor VIII.
44. 45. The method of claim 40, wherein treatment comprising Factor VIII bypass 5 therapy is assigned to an individual with a predicted increased risk of developing antibodies against Factor VIII.
45. 46. The method of claim 40, wherein assigning treatment comprises adjusting a dosage and/or frequency of Factor VIII administration based on the predicted risk of developing antibodies against Factor VIII.

    0
46. 47. The method of claim 46, wherein adjusting a dosage of Factor VIII comprises increasing the dosage and/or frequency of Factor VIII administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII.
47. 48. The method of claim 46, wherein adjusting a dosage of Factor VIII comprises decreasing the dosage and/or frequency of Factor VIII administered to an individual

    5 with a predicted increased risk of developing antibodies against Factor VIII.
48. 49. The method of claim 40, wherein assigning treatment comprises adjusting a dosage and/or frequency of a non-Factor VIII hemostatic agent administration based on the predicted risk of developing antibodies against Factor VIII.
49. 50. The method of claim 46, wherein adjusting a dosage of a non-Factor VIII 20 hemostatic agent comprises decreasing the dosage and/or frequency of a non-Factor VIII hemostatic agent administered to an individual with a predicted decreased risk of developing antibodies against Factor VIII.
50. 51. The method of claim 46, wherein adjusting a dosage of a non-Factor VIII hemostatic agent comprises increasing the dosage and/or frequency of a non-Factor VIII

    25 hemostatic agent administered to an individual with a predicted increased risk of developing antibodies against Factor VIII.

    295

    WO 2011/131774

    PCT/EP2011/056471
51. 52. An oligonucleotide from 10 to 60 nucleotides in length that contacts at _H least one single nucleotide polymorphism (SNP) selected from the group consisting of the SNPs listed in Table 1.
52. 53. A diagnostic kit for predicting the risk of developing antibodies against

    5 Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the kit comprising at least one oligonucleotide capable of being used to detect at least one single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4.
53. 54. The diagnostic kit of claim 53, wherein the SNP is selected from the group 0 consisting of rsl2368829, rsll744216, rsl863993, rs4147385, rsl2546235, rs4242389, rsl0054825, rsl7535213, rsl0072056, and rsl7725712.
54. 55. The diagnostic kit of claim 53 or 54, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsl2368829.
55. 56. The diagnostic kit according to any one of claims 53 to 55, wherein the kit 5 comprises an oligonucleotide capable of being used to detect SNP rsl 1744216.
56. 57. The diagnostic kit according to any one of claims 53 to 56, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsl863993.
57. 58. The diagnostic kit according to any one of claims 53 to 57, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rs4147385.

    20
58. 59. The diagnostic kit according to any one of claims 53 to 58, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsl2546235.
59. 60. The diagnostic kit according to any one of claims 53 to 59, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rs4242389.
60. 61. The diagnostic kit according to any one of claims 53 to 60, wherein the kit 25 comprises an oligonucleotide capable of being used to detect SNP rsl0054825.

    296

    WO 2011/131774

    PCT/EP2011/056471

    2019226219 06 Sep 2019
61. 62. The diagnostic kit according to any one of claims 53 to 61, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsl7535213.
62. 63. The diagnostic kit according to any one of claims 53 to 62, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsl0072056.

    5
63. 64. The diagnostic kit according to any one of claims 53 to 63, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rs 17725712.
64. 65. A diagnostic kit for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with severe Hemophilia, the kit comprising at least one oligonucleotide capable of being used to detect at least one single nucleotide

    0 polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4.
65. 66. The diagnostic kit of claim 65, wherein the SNP is selected from the group consisting of rsl2368829, rs4147385, rsl 1744216, rsl863993, rsl7535213, rsl0072056, rsl0054825, rsl2546235, rs4242389, rs2071336, rs414634, rsl7725712, rsl 1773821,

    5 rs8005905, and rs9482888.
66. 67. The diagnostic kit of claim 65 or 66, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsl2368829.
67. 68. The diagnostic kit according to any one of claims 65 to 67, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rs4147385.

    20
68. 69. The diagnostic kit according to any one of claims 65 to 68, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsl 1744216.
69. 70. The diagnostic kit according to any one of claims 65 to 69, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsl863993.
70. 71. The diagnostic kit according to any one of claims 65 to 70, wherein the kit

    25 comprises an oligonucleotide capable of being used to detect SNP rs!7535213.

    297

    WO 2011/131774

    PCT/EP2011/056471

    2019226219 06 Sep 2019
71. 72. The diagnostic kit according to any one of claims 65 to 71, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsl0072056.
72. 73. The diagnostic kit according to any one of claims 65 to 72, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsl0054825.

    5
73. 74. The diagnostic kit according to any one of claims 65 to 73, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsl2546235.
74. 75. The diagnostic kit according to any one of claims 65 to 74, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rs4242389.
75. 76. The diagnostic kit according to any one of claims 65 to 75, wherein the kit 0 comprises an oligonucleotide capable of being used to detect SNP rs2071336.
76. 77. The diagnostic kit according to any one of claims 65 to 76, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rs414634.
77. 78. The diagnostic kit according to any one of claims 65 to 77, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rs 17725712.

    5
78. 79. The diagnostic kit according to any one of claims 65 to 78, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rsll773821.
79. 80. The diagnostic kit according to any one of claims 65 to 79, wherein the kit comprises an oligonucleotide capable of being used to detect SNP rs8005905.
80. 81. The diagnostic kit according to any one of claims 65 to 80, wherein the kit 20 comprises an oligonucleotide capable of being used to detect SNP rs9482888..
81. 82. The diagnostic kit according to any one of claims 53 to 81, wherein the oligonucleotide flanks the position of the SNP in the genome.
82. 83. The diagnostic kit according to any one of claims 53 to 81, wherein the oligonucleotide overlaps the position of the SNP in the genome.

    298

    WO 2011/131774

    PCT/EP2011/056471
83. 84. A microarray for predicting the risk of developing antibodies against _H Factor VIII (FVIII) in an individual diagnosed with Hemophilia, the microarray comprising a support having a plurality of discrete regions, each discrete region having a nucleic acid fragment spotted thereon, wherein at least one nucleic acid fragment spotted on the support

    5 comprises a sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 1, a SNP listed in Table 2, a SNP listed in Table 3, and a SNP listed in Table 4.
84. 85. The microarray of claim 84, wherein the SNP is selected from the group consisting of rsl2368829, rsll744216, rsl863993, rs4147385, rsl2546235, rs4242389,

    0 rsl0054825, rsl7535213, rsl0072056, and rsl7725712.
85. 86. A microarray for predicting the risk of developing antibodies against Factor VIII (FVIII) in an individual diagnosed with severe Hemophilia, the microarray comprising a support having a plurality of discrete regions, each discrete region having a nucleic acid fragment spotted thereon, wherein at least one nucleic acid fragment spotted on the support

    5 comprises a sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) selected from the group consisting of a SNP listed in Table 2 and a SNP listed in Table 4.
86. 87. The microarray of claim 86, wherein the SNP is selected from the group consisting of rsl2368829, rs4147385, rsi 1744216, rsl863993, rsl7535213, rsl0072056,

    20 rsl0054825, rsl2546235, rs4242389, rs2071336, rs414634, rsl7725712, rsi 1773821, rs8005905, and rs9482888.
87. 88. The microarray according to any one of claims 84 to 87, wherein the sequence that is complementary to a genomic sequence that flanks a single nucleotide polymorphism (SNP) includes a nucleotide corresponding to the position of the SNP in the

    25 genome.