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WO2012001613A1 - Combinaison de six snp destinée à la détection de la prédisposition pour des maladies neurovasculaires - Google Patents

Combinaison de six snp destinée à la détection de la prédisposition pour des maladies neurovasculaires Download PDF

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WO2012001613A1
WO2012001613A1 PCT/IB2011/052818 IB2011052818W WO2012001613A1 WO 2012001613 A1 WO2012001613 A1 WO 2012001613A1 IB 2011052818 W IB2011052818 W IB 2011052818W WO 2012001613 A1 WO2012001613 A1 WO 2012001613A1
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snps
individual
stroke
neurovascular
risk
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Joan Montaner Villalonga
Sophie Domingues
Israel FERNÁNDEZ CADENAS
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Fundacio Institut de Recerca Hospital Universitari Vall dHebron
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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6813—Hybridisation assays
    • C12Q1/6827—Hybridisation assays for detection of mutation or polymorphism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to the detection of a predisposition to neurovascular diseases in an individual, in particular stroke.
  • the present invention relates to a method and a kit for detecting a predisposition to stroke in an individual, comprising the detection of a combination of six single nucleotide polymorphisms (SNPs), namely rs2276109, rs7956957, rs310585, rsl0275136, rs5742912 and rsl0947803, as well as the combination itself, the polynucleotides comprising them and their uses.
  • SNPs single nucleotide polymorphisms
  • Neurovascular diseases are a huge public health burden worldwide.
  • neurovascular accidents, or strokes are the 3 rd cause of death and 1 st cause of disability, showing a negative impact not only on the quality of life of the affected patient but also on the family, with a large number of patients suffering functional dependence even more than one year after the event [1].
  • the cost for health care systems is severe because there are direct costs (hospital stay, rehabilitation, transportation, medical monitoring, pharmaceutical consumption, etc.), and indirect costs (lost of productivity of patients and caregivers, loss of activity, premature mortality, etc.).
  • the estimated cost of stroke in Spain is 13,826 € the first year, 8,945 € the second year and 7,739 € the third year per patient [2]. Therefore, a need exists for detecting and preventing stroke.
  • the present inventors have selected to explore neurovascular accidents prevention from a genetic point of view. Indeed, there is an important genetic implication in neurovascular diseases, discovered in the early nineties by twin and familiar aggregation studies, but the genes responsible for the inheritance remain largely undetermined [3]. For instance, the classical linkage analysis and candidate gene association approaches have reported an association of the PDE4D, ALOX5AP, ApoE, IL6, MTHFR or TNFa genes with ischemic stroke, but replication of these findings has been really inconsistent [4]. Moreover, genome-wide association studies (GWAS) have revealed the association of two SNPs with stroke within chromosome 12pl3 in Caucasians, suggesting a role for the NINJ2 gene [5], an association that has been later contradicted [6].
  • GWAS genome-wide association studies
  • neurovascular diseases share common demographical and clinical risk factors such as the presence of transient ischemic attacks, hypertension, dyslipidemia, diabetes, atrial fibrillation, cardiac disease, amyloid angiopathy, obesity, drug use or abuse, sedentary life style, smoking, medication, alcohol consumption and/or familiar antecedents [3].
  • a first object of the present invention is to provide new genetic markers for neurovascular diseases detection.
  • a second object of the present invention is to provide a new method and a new kit for determining the probability of suffering a neurovascular accident, or stroke.
  • the present inventors have surprisingly found that the combination of six SNPs disclosed in the present invention is useful for determining the risk of suffering a neurovascular accident, or stroke, and consequently a method and a kit using said combination can be developed.
  • the present invention relates to the combination of six single nucleotide polymorphisms (SNPs), namely rs2276109, rs7956957, rs310585, rsl0275136, rs5742912 and rsl0947803, indicative of an individual's risk of neurovascular diseases.
  • SNPs single nucleotide polymorphisms
  • the present invention also relates to a method for determining a genetic predisposition to neurovascular diseases in an individual, comprising detecting the alleles of the six SNPs rs2276109, rs7956957, rs310585, rsl0275136, rs5742912 and rsl0947803 in an isolated nucleic acid sample of an individual.
  • the present invention further relates to a kit for determining an individual's risk for a neurovascular disease.
  • the present invention also relates to the use of the combination mentioned above.
  • Figure 2 Percent of controls and stroke cases depending on the number of genetic variants carried.
  • Figure 3 Percent of controls and stroke cases depending on the total number of risk factors carried.
  • Figure 5 Percent of controls and stroke cases in each category proposed by the stroke risk model.
  • eNaC epithelial sodium channel
  • MMP matrix metalloproteinase
  • ALOX5AP Arachidonate 5-lipoxygenase-activating protein
  • APOE apolipoprotein E
  • CELSR1 cadherin EGF lag seven-pass G-type receptor 1
  • IL6 interleukin 6
  • KCNK17 potassium channel, subfamily K, member 17
  • LRP1 low density lipoprotein receptor-related protein 1
  • MMP12 matrix metalloproteinase 12
  • NINJ2 nerve injury-induced protein 2
  • NOS3 nitric oxide synthase 3
  • PDE4D phosphodiesterase 4D
  • PITX2 paired-like homeodomain transcription factor 2
  • PRKCH protein kinase C, eta
  • SCNN1A sodium channel, nonvoltage-gated 1, alpha subunit
  • TNFa tumor necrosis factor alpha
  • ZFHX3 zinc finger homeobox 3
  • allele refers to a sequence variant of the gene.
  • polymorphic and polymorphism refer to the condition in which two or more variants of a specific genomic sequence, or the encoded amino acid sequence, can be found in a population.
  • the terms refer either to the nucleic acid sequence or the encoded amino acid sequence; the use will be clear from the context.
  • the polymorphic region or polymorphic site refers to a region of the nucleic acid where the nucleotide difference that distinguishes the variants occurs, or, for amino acid sequences, a region of the amino acid where the amino acid difference that distinguishes the protein variants occurs.
  • a “single nucleotide polymorphism” or "SNP” refers to a polymorphic site consisting of a single nucleotide position.
  • genotype refers to a description of the alleles of a gene or genes contained in an individual or a sample. As used herein, no distinction is made between the genotype of an individual and the genotype of a sample originating from the individual. Although typically a genotype is determined from samples of diploid cells, a genotype can be determined from a sample of haploid cells, such as a sperm cell.
  • genotype ratio or “OR” refers to the ratio of the odds of the disease for individuals with the marker (polymorphism) relative to the odds of the disease in individuals without the marker (polymorphism).
  • isolated polynucleotide acid or "isolated nucleic acid”, as used herein, is referred to a polynucleotide that is separated and/or recovered from a nucleic acid from nucleotide sequences which normally flank the nucleic acid molecule and/or has been completely or partially purified from other biological material (e.g. protein) normally associated with the nucleic acid.
  • isolated polynucleotide acid comprises polynucleotide variants wherein one or more insertions, deletions and/or substitutions have been carried out.
  • oligonucleotide is meant a single- stranded nucleotide polymer made of more than 2 nucleotide subunits covalently joined together.
  • gene refers not only to the strictly coding part but also the non-coding parts.
  • the term "a combination of six" SNPs is not intended to mean a closed group of a maximum of 6 SNPs or the corresponding polynucleotides, but it can also include combinations with more SNPs or the corresponding polynucleotides. In these combinations, the SNPs or the corresponding polynucleotides can be included or not in stroke-associated genes, providing that said six SNPs correspond to the SNPs and the corresponding polynucleotides disclosed in the present invention.
  • clinical variable is meant the use of demographic data indicative of stroke such as race or ethnic origin, age, gender and familial history of stroke, as well as the use of clinical information such as the presence of transient ischemic attacks, hypertension, dyslipidemia, diabetes, atrial fibrillation, cardiac disease, amyloid angiopathy, obesity, drug use or abuse, sedentary life style, smoking, medication, alcohol consumption and antecedents of stroke.
  • stroke-associated genes genes that have been reported to be involved in the processes of stroke and in processes functionally related to stroke such as inflammation, fibrinolysis, coagulation, hypertension, heart disease, angiogenesis, lipid metabolism or diabetes.
  • neurovascular diseases refers to complex disorders of the brain, spinal cord and/or blood vessels and risk factors associated with complex disorders of the brain, spinal cord and/or blood vessels such as: stroke, arteriovenous malformations, thrombosis, CADASIL, cerebral amyloid angiopathy, aneurysms, dissections, hyper/hypotension, encephalopathies, lacunar syndromes, Fabry, homocystinuria/homocysteinemia, hyperglycemia/hypoglycemia, hyper/hypolipidemia, diabetes, MELAS, methylmalonic acidemia, fibromuscular dysplasia, foix-alajouanine syndrome, reperfusion injury, hemorrhagic stroke, ischemic stroke, cardioembo
  • the present invention relates to a combination of six SNPs, namely rs2276109, rs7956957, rs310585, rsl0275136, rs5742912 and rsl0947803, indicative of an individual's risk of neurovascular diseases.
  • said six SNPs are combined with one or more of the SNPs rs7193343, rs6007897, rs4044210, rsl 1064005, rs22381 12, rsl2319392, rs2228576, rs9634156, rsl3376333, rs6725887, rs2306374, rsl2526453, rs3798220, rsl 122608, rs9982601, rsl 801282, rs5219, rs3754777, rsl3333226, rs4977574, rsl0012946.
  • said single nucleotide polymorphisms according to the previous embodiments are combined with one or more clinical variables associated with a neurovascular disease.
  • said clinical variable is selected from age, gender, smoking, hypertension, diabetes and dyslipidemic status.
  • said neurovascular disease in the previous embodiments is stroke.
  • the present invention also relates to the combination of six isolated polynucleotides included in neurovascular disease-associated genes comprising each of said polynucleotides a SNP selected from SNPs rs2276109, rs7956957, rs310585, rsl0275136, rs5742912 and rsl0947803, indicatives of an individual's risk of neurovascular disease, said isolated polynucleotides corresponding to SEC ID No. 1 to 6.
  • said neurovascular disease is stroke.
  • SEC ID No. 1 indicates the position of polymorphism rs2276109 in its surrounding sequence, wherein the nucleotide N is the SNP at position 21 and can be a A or G nucleotide, being G the allele associated with neurovascular disease.
  • rs2276109 is located on human contig NT 033899.7 at chromosomal position 102251001 on chromosome 1 1.
  • SEC ID No. 2 indicates the position of polymorphism rs 10275136 in its surrounding sequence, wherein the nucleotide N is the SNP at position 21 and can be a T or C nucleotide, being C the allele associated with neurovascular disease, rs 10275136 is located on human contig NT 007914.14 at chromosomal position 150514825 on chromosome 7.
  • SEC ID No. 3 indicates the position of polymorphism rs310585 in its surrounding sequence, wherein the nucleotide N is the SNP at position 21 and can be a G or A nucleotide, being A the allele associated with neurovascular disease.
  • rs310585 is located on human contig NT 007914.14 at chromosomal position 150526188 on chromosome 7.
  • SEC ID No. 4 indicates the position of polymorphism rs7956957 in its surrounding sequence, wherein the nucleotide N is the SNP at position 21 and can be a C or G nucleotide, being G the allele associated with neurovascular disease.
  • rs7956957 is located on human contig NT 029419.1 1 at chromosomal position 55889082 on chromosome 12.
  • SEC ID No. 5 indicates the position of polymorphism rs 10947803, also called rs9471058, in its surrounding sequence, wherein the nucleotide N is the SNP at position 21 and can be a C or A nucleotide, being A the allele associated with neurovascular disease, rs 10947803 is located on human contig NT 007592.14 at chromosomal position 39378588 on chromosome
  • SEC ID No. 6 indicates the position of polymorphism rs5742912 in its surrounding sequence, wherein the nucleotide N is the SNP at position 21 and can be a C or T nucleotide, being T the allele associated with.
  • rs5742912 is located on human contig NT 009759.15 at chromosomal position 632861 1 on chromosome 12.
  • said neurovascular disease in SEC ID No. 1-6 is stroke
  • said neurovascular disease is stroke.
  • the alleles of said SNPs are inferred by genetic testing of other markers or by measuring the levels of activity or concentration of the proteins or corresponding RNA expression levels of NOS3, SCNN1A, KCNK17, MMP12 and/or LRP.
  • said combination of SNPs or the corresponding isolated polynucleotides is found in an individual belonging to the Mediterranean population.
  • said individual belongs to the Spanish population.
  • said combination of SNPs or the corresponding isolated polynucleotides can then be applied to a new model or method for determining the genetic risk that an individual may present for suffering a neurovascular disease, preferably stroke, and a kit for implementing said method.
  • the aim of this study was to create a genetic predictive model for stroke, although extendable to a neurovascular disease as defined herein, by discovering a new combination of genetic markers through one of the largest candidate gene association studies ever performed in stroke, including a replication in new individuals from Spain and Portugal and a functional analysis of the results.
  • a case-control study design was used to analyze genetic variants in Spanish and Portuguese populations. Sample size was calculated with the Ene 2.0 software to obtain a power of 0.80 with a significance level of 0.05 for a 6% difference of alleles' frequency between cases and controls.
  • 221 SNPs in 135 different candidate genes were chosen in the literature for their putative functions in neurovascular diseases and in processes functionally related to these diseases such as inflammation, fibrinolysis, coagulation, hypertension, coronary heart disease, angiogenesis, lipid metabolism or diabetes and were genotyped and analyzed as described below.
  • Genomic DNA was extracted for each subject from lmL of peripheral blood anti- coagulated with EDTA by standard methods.
  • the SNPs were genotyped by SNPlexTM (Applied Biosystems, Inc., Foster City, USA) at the Spanish national genotyping centre (CeGen), Sequenom ® iPLEX or TaqMan ® (Applied Biosystems) with call rates >90%.
  • Five genes were analyzed entirely by Tag-SNPs, defined by the HapMap data using pairwise tagger r 2 >0.8 and a minor allele frequencyX).1 : the MMP9, NOS3, VEGF, LRP and IL6 genes. Deviation from the Hardy- Weinberg equilibrium (HWE) was assessed using a ⁇ 2 test with 1 degree of freedom.
  • the analysis was performed under an additive model, considering stage 1, stage 2 and the overall database. A logistic regression was then performed for each variable and the predicted probabilities were recorded.
  • the combination of genetic and clinical variants carried by each individual was used to develop a predictive model of stroke risk and to determine stroke risk categories.
  • RiboPure- BloodTM Kit RiboPure- BloodTM Kit (Ambion®, Foster City, USA).
  • cDNA synthesis was performed using a High- Capacity cDNA Archive Kit (Applied Biosystems Inc., Foster City, USA).
  • mRNA levels were determined by quantitative Real Time PCR, using a standard TaqMan® PCR kit protocol and TaqMan fluorogenic probes (LRP: Hs00233856_ml, SCNN1A: Hs00168906_ml, MMP12: Hs00159178_ml) with a 7500 Real Time PCR System (Applied Biosystems Inc., Foster City, USA).
  • the Cyclophilin A (PPIA) was run as housekeeping gene to normalize the results (Hs99999904_ml). All reactions were run in triplicates on 96-well plates, and analyzed using the Applied Biosystems SDS 7500 system software (Applied Biosystems Inc., Foster City, USA). The results are expressed in percentage compared to a unique calibrator sample used in all experiments.
  • MMP12 protein level was measured from serum of controls by Fuorokine® MMP12 Analyte Profiling in 96-well microtiter plates. Each sample was concentrated from 500 ⁇ to lOOuL with Microcon® (MilliporeTM, Billerica, USA) and tested twice following manufacturer's users' guide on a Luminex analyzer (Human MMP Base Kit, Fluorokine® MAP, R&D Systems, Minneapolis, USA). NOS3 protein activity was assayed from plasma of controls by Nitrate/Nitrite Colorimetric Assay Kit in 96-well microtiter plates. Each sample was concentrated from 500 ⁇ to lOOuL with Microcon® (MilliporeTM, Billerica, USA) and tested twice following manufacturer's users' guide (Catalog n°780001, CaymanTM, Ann Arbor, USA).
  • Raw expression values obtained directly from .CEL files were pre-processed using the RMA method, a three-step process which integrates background correction, normalization and summarization of probe values. These normalized values were the basis for all the analysis. Previous to any analysis, data were submitted to non-specific filtering to remove low signal genes and low variability genes. The selection of differentially expressed genes between conditions was based on a linear model analysis with empirical Bayes moderation of the variance estimates following the methodology developed by Smyth. This method combines information from the whole array and every individual gene in order to obtain improved error estimates which are very useful in microarray data analysis where sample sizes are often small what can lead to erratic error estimates and, in consequence, to untruthful p-values. Fold changes, (moderated)-t or p-values were used to rank the genes from most to least differentially expressed. In order to deal with the multiple testing issues, p-values were adjusted using the false discovery rate (FDR) method by Benjamini and Hochberg.
  • FDR false discovery rate
  • IP A Ingenuity Pathways software
  • MMP12 gene expression could not be detected in 12 healthy controls.
  • MMP12 protein level was determined in 14 healthy controls by Luminex and we could detect a slight presence of MMP12 in 6 samples but no association with rs2276109 genotypes was observed (AA: 22.4 ⁇
  • microarrays analysis in 12 subjects revealed that rs7956957 genotypes of the LRP gene were associated with the expression of several genes after correction by false discovery rate (FDR) and the Ingenuity Pathway Analysis (IP A) software identified several networks associated with the LRP genotypes. Noticeably, the risk allele of the rs7956957 SNP
  • G allele was associated with lower expression of genes involved in inflammatory processes, such as CLEC4C, complements 4A and 4B (C4A and C4B), while it was associated with higher expression of genes involved in apoptosis such as ITGB3, ALOX12, NEK1 or G0S2. Moreover, the expression of eight genes was in concordance in both the CG vs. CC and GG vs. CC comparisons. 2.3.- Discussion
  • the inventors analyzed the association of 221 SNPs functionally related to neurovascular diseases in two Mediterranean populations. After a multivariate analysis, adjusted for conventional risk factors, the inventors could replicate a statistically significant association between six SNPs (rs2276109, rs7956957, rs310585, rsl0275136, rs5742912 and rsl0947803) in the Spanish population and one SNP (rs2276109) in the Portuguese population, although another SNP (rs7956957) showed a strong trend to association and the risk of neurovascular accident, or stroke.
  • the rs5742912 of SCNNIA is an important structural change of amino-acid from tryptophan to arginine (Trp493- ⁇ Arg), so from cyclic non-polar to positively charged.
  • the gene codes for a subunit of the eNaC protein, a nonvoltage-gated sodium channel, which is present in epithelial cells, together with two other subunits, SCNN1B and SCNNIG [17].
  • the role of this protein in sodium homeostasis, plasma osmolality and blood pressure regulation has converted it into an ideal study candidate for the development of complex diseases such as stroke, myocardial infarction or renal failure [18].
  • the eNaC is responsible for the rate- limiting step of sodium reabsorption and is sensitive to amiloride, a diuretic that can block the channel and inhibit sodium assimilation, used in the management of hypertension and congestive heart failure [19].
  • amiloride a diuretic that can block the channel and inhibit sodium assimilation, used in the management of hypertension and congestive heart failure [19].
  • the rs5742912 SNP of SCNNIA has been associated with ischemic stroke [1 1].
  • SNP located in chromosome 12 was associated with ischemic stroke in our study. Indeed, the G allele of the rs7956957 in LRP1 at 12ql3 was identified as a risk variant in all stages of our study and in all stroke etiologies, although it was not associated to mRNA levels.
  • the SNP is in weak linkage with many other SNPs, although the only functional SNP (C766T or rs 1799986) described is located in another region of the gene, which spans 89 exons, and is not in linkage disequilibrium with the rs7956957 SNP.
  • rs7956957 The effect of the rs7956957 on IS development was further examined through microarrays and we identified several interesting genes which presented different levels of expression depending on the rs7956957 genotypes such as ALOX12, ITGB3, MPL, C4A and C4B.
  • a merged representation of the two main networks identified by the IPA software revealed that the genes involved could have an important role in biological processes such as apoptosis, cell signaling, cell death and inflammation.
  • the merge also indicate that some genes such as LDL, NFKB, CDKNIA, and p38-MAPK could be important regulators in these networks.
  • MMP12 and NOS3 Two other genes that have been identified in our study, MMP12 and NOS3, are both involved in processes of inflammation.
  • the MMP12 protein has been related to ischemic stroke thanks to its role in atherosclerotic plaque stability , while the MMP12 gene, located at chromosome l lq22 and also called human macrophage metalloelastase, has been related to coronary artery disease and hemorrhagic stroke [23-24].
  • the rs2276109 SNP that was associated with ischemic stroke in our cohort is a A to G substitution in the promoter region of the gene, and has been shown to be functional, by influencing the capacity of binding of the transcription factor activated protein- 1 (AP-1) in electromobility shift assays [25].
  • the A allele was associated with higher MMP12 promoter activity in vitro in transient transfection studies, and was associated with lower risk of ischemic stroke in our study, since the G allele was the less frequent risk allele. It thus seems that lower MMP12 promoter activity, through the G allele of the rs2276109 SNP, could be associated with higher ischemic stroke risk, but this hypothesis needs to be confirmed in further studies. We did intend to measure MMP12 gene expression and protein levels in healthy controls in our study, in order to understand better the contribution of the rs2276109 variant, but mRNA levels and protein levels were barely detectable and insufficient to draw any conclusion.
  • NOS3 nitric oxide synthase 3
  • eNOS endothelial NOS
  • cNOS constitutive NOS
  • KCNK17 mRNA presented higher levels of KCNK17 mRNA than C carriers. It is thus possible that higher mRNA levels of the KCNK17 gene are associated with a higher risk of ischemic stroke.
  • the mechanism is unknown for the function of the rs 10947803 variant.
  • the SNP is intronic and thus does not belong to the promoter region.
  • the protein coded by the KCNK17 gene is a member of the 2-pore domain superfamily of K + channels [31-32].
  • the combination of six SNPs disclosed above allows foreseeing the individual's risk for stroke in a ratio at least 26 times higher than a person which, at the same environmental conditions, does not present any of these SNPs.
  • this odd ratio dramatically and surprisingly increases as the number of SNPs increases, not just through a summatory effect, but through a multiplicative effect, the optimal model being when the number of SNPs is six.
  • the combination of two, three, four, or five SNPs is gradually better up to six SNPs disclosed herein which is the optimal combination to predict the risk of stroke.
  • the present invention also relates to a method for determining a genetic predisposition to neurovascular diseases in an individual, comprising detecting the alleles of six SNPs consisting of rs2276109, rs7956957, rs310585, rsl0275136, rs5742912 and rsl0947803 in an isolated nucleic acid sample of an individual.
  • the present method of detection may be carried out with less SNPs, only the combination of the six SNPs used herein provides efficient and satisfactory results.
  • the alleles detected according to the embodiments for the method of the present invention are a G allele for rs7956957, A allele for rs310585, G allele for rs2276109, C allele for rs 10275136, T allele for rs5742912 or A allele for rs 10947803.
  • the isolated nucleic acid sample of the individual used in any of the embodiments for the method of the present invention may comprise DNA or RNA.
  • said nucleic acid sample can be amplified, usually by a polymerase chain reaction (PCR) in the way well known in the art.
  • PCR polymerase chain reaction
  • SNPs can be carried out by any of the methods well known in the art, for example, without being limited to, hybridization of a nucleic acid probe or oligonucleotide sequence, or by radioactive, enzymatic, luminescent or fluorescent markers [35: page 4183 and 36: pages 246-247].
  • Said probe or oligonucleotide sequence comprises a sequence that is fully complementary to a nucleic acid sequence comprising the SNPs disclosed in the present invention (SEC ID No. 1 to SEC ID No. 6).
  • the present invention relates to the method according to any of the embodiments disclosed above wherein the six SNPs are combined with one or more clinical variables associated with a neurovascular disease.
  • said clinical variables are selected from age, gender, smoking, hypertension, diabetes and dyslipidemic status.
  • the present invention relates to the method according to any of the embodiments disclosed above wherein the alleles of said SNPs are inferred by genetic testing.
  • the present invention relates to the method according to any of the embodiments disclosed above wherein the alleles of said SNPs are inferred from the levels of activity or concentration of the proteins or corresponding RNA expression levels of NOS3, SCNN1A, KCNK17, MMP12 and/or LRP, which are modulated by the presence of the genetic markers, as shown in the results section.
  • the present invention relates to the method according to any of the embodiments disclosed above wherein said six SNPs are combined with SNPs rs7193343, rs6007897, rs4044210, rsl l064005, rs22381 12, rsl2319392, rs2228576, rs9634156, rsl3376333, rs6725887, rs2306374, rsl2526453, rs3798220, rsl 122608, rs9982601, rsl 801282, rs5219, rs3754777, rsl3333226, rs4977574, rsl0012946.
  • the present invention relates to the method according to any of the embodiments disclosed above further comprising comparing the combination of alleles obtained to that of other individuals affected by neurovascular diseases, and detecting a genetic predisposition to a neurovascular disease if the individual to be diagnosed presents the same genetic background as affected individuals.
  • said other individuals have a blood relationship with the individual.
  • said neurovascular disease is stroke.
  • the method according to any of the embodiments disclosed above for determining an individual's risk for a neurovascular disease, preferably stroke, is applied to an individual belonging to the Mediterranean population.
  • said individual belongs to the Spanish population.
  • the present invention further relates to a kit for determining an individual's risk for a neurovascular disease comprising:
  • kits for use the kit to determine the individual's risk of stroke considering the combination of SNPs carried.
  • Said six probes in the kit can be labeled.
  • the kit can comprise reagents such as dilution buffers, reaction buffers, polymerase enzymes and/or primers.
  • reagents such as dilution buffers, reaction buffers, polymerase enzymes and/or primers.
  • hybridization can be detected by autoradiography, scintillation, counting or gamma counting.
  • the kit can further comprise amplification or sequencing primers which can be sequence-specific.
  • the kit can also comprise reagents for labeling one or more of the sequence-specific oligonucleotides, or comprise labeled sequence-specific oligonucleotides.
  • Useful labels include radioisotopes as well as non-radioactive reporting groups. Isotopic labels include 3 H,
  • Isotopic labels can be introduced into the oligonucleotide by techniques known in the art.
  • Non-isotopic labels include fluorescent molecules, chemiluminiscent molecules, enzymes, cofactors, enzyme substrates, haptens or other ligands.
  • the present invention relates to the kit according to any of the embodiments disclosed above wherein the six SNPs are combined with one or more clinical variables associated with a neurovascular disease.
  • said clinical variables are selected from age, gender, smoking, hypertension, diabetes and dyslipidemic status.
  • the alleles of said SNPs are inferred by genetic testing of other markers or by measuring the levels of activity or concentration of the proteins or corresponding RNA expression levels of NOS3, SCNN 1 A, KCNK 17, MMP 12 and/or LRP.
  • said neurovascular disease is stroke.
  • said kit for determining an individual's risk for neurovascular disease, preferably stroke is applied to an individual belonging to the Mediterranean population.
  • said individual belongs to the Spanish population.
  • the present invention further relates to the use of the combination of six SNPs rs2276109, rs7956957, rs310585, rsl0275136, rs5742912 and rsl0947803 and all the combination embodiments disclosed herein in a kit for determining an individual's risk for a neurovascular disease, preferably stroke.
  • said use is applied to an individual belonging to the Mediterranean population.
  • said individual belongs to the Spanish population.
  • the present invention further relates to the use of the combination of the six SNPs rs2276109, rs7956957, rs310585, rsl0275136, rs5742912 and rsl0947803, indicative of an individual's risk of neurovascular disease, preferably stroke, and all the combination embodiments disclosed herein as a genetic testing tool for a neurovascular disease, preferably stroke.
  • said use is applied to an individual belonging to the Mediterranean population.
  • said individual belongs to the Spanish population.
  • Lumley T Folsom AR, van den Herik EG, Bos MJ, Beiser A, Cushman M, Launer LJ, Shahar E, Struchalin M, Du Y, Glazer NL, Rosamond WD, Rivadeneira F, Kelly-Hayes M, Lopez OL, Coresh J, Hofman A, DeCarli C, Heckbert SR, Koudstaal PJ, Yang Q, Smith NL, Kase CS, Rice K, Haritunians T, Roks G, de Kort PL, Taylor KD, de Lau LM, Oostra BA,
  • Mitochondrial haplogroup HI is protective for ischemic stroke in Portuguese patients. BMC Med Genet. 2008; 9:57.
  • Lamblin N Bauters C
  • Hermant X Lablanche JM
  • Helbecque N Amouyel P.
  • Endothelial nitric oxide synthase gene polymorphisms and cardiovascular disease a HuGE review. Am J Epidemiol. 2006; 164:921-935.
  • n a or g
  • n t or c
  • n g or a
  • n c or g
  • n c or a
  • n c or t

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Abstract

La présente invention concerne la combinaison de six polymorphismes de nucléotide unique (SNP), c'est-à-dire rs2276109, rs7956957, rs310585, rsl0275136, rs5742912 et rsl0947803, indicatrice d'un risque d'un individu vis-à-vis de maladies neurovasculaires. La présente invention concerne également un procédé de détermination d'une prédisposition génétique pour des maladies neurovasculaires chez un individu, comprenant la détection des allèles des six SNP rs2276109, rs7956957, rs310585, rsl0275136, rs5742912 et rsl0947803 dans un échantillon d'acides nucléiques isolé d'un individu. La présente invention concerne en outre une trousse pour la détermination du risque d'un individu vis-à-vis d'une maladie neurovasculaire. La présente invention concerne également l'utilisation de la combinaison mentionnée ci-dessus.
PCT/IB2011/052818 2010-06-29 2011-06-27 Combinaison de six snp destinée à la détection de la prédisposition pour des maladies neurovasculaires Ceased WO2012001613A1 (fr)

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EP2873738A1 (fr) 2013-11-15 2015-05-20 Latvian Biomedical Research and Study Centre Composition SNP et procédé permettant de diagnostiquer un risque de dyslipidémie
US9904000B2 (en) 2014-12-09 2018-02-27 Samsung Electronics Co., Ltd. Display device and backlight unit included therein
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WO2023205243A1 (fr) * 2022-04-19 2023-10-26 The Regents Of The University Of Michigan Détermination du risque de dysplasie fibromusculaire et systèmes et procédés d'utilisation associés
EP4269601A2 (fr) 2015-03-27 2023-11-01 President and Fellows of Harvard College Cellules t modifiées, leurs procédés de préparation et utilisation
EP4286517A2 (fr) 2013-04-04 2023-12-06 President and Fellows of Harvard College Utilisations thérapeutiques de l'édition de génome au moyen de systèmes crispr/cas
US11913015B2 (en) 2017-04-17 2024-02-27 University Of Maryland, College Park Embryonic cell cultures and methods of using the same

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EP2843056A1 (fr) * 2013-08-30 2015-03-04 Gendiag.exe, S.L. Marqueurs de risque de maladie cardiovasculaire chez des patients atteints de maladie rénale chronique
WO2015028612A1 (fr) * 2013-08-30 2015-03-05 Gendiag.Exe, S.L. Marqueurs de risque pour la maladie cardio-vasculaire chez des patients atteints de maladie rénale chronique
EP2873738A1 (fr) 2013-11-15 2015-05-20 Latvian Biomedical Research and Study Centre Composition SNP et procédé permettant de diagnostiquer un risque de dyslipidémie
US10670611B2 (en) 2014-09-26 2020-06-02 Somalogic, Inc. Cardiovascular risk event prediction and uses thereof
US9904000B2 (en) 2014-12-09 2018-02-27 Samsung Electronics Co., Ltd. Display device and backlight unit included therein
EP4269601A2 (fr) 2015-03-27 2023-11-01 President and Fellows of Harvard College Cellules t modifiées, leurs procédés de préparation et utilisation
US11913015B2 (en) 2017-04-17 2024-02-27 University Of Maryland, College Park Embryonic cell cultures and methods of using the same
WO2023205243A1 (fr) * 2022-04-19 2023-10-26 The Regents Of The University Of Michigan Détermination du risque de dysplasie fibromusculaire et systèmes et procédés d'utilisation associés

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