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WO2012113948A1 - Procédé pour la détermination de la prédisposition génétique à la maladie de parkinson - Google Patents

Procédé pour la détermination de la prédisposition génétique à la maladie de parkinson Download PDF

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WO2012113948A1
WO2012113948A1 PCT/ES2012/000039 ES2012000039W WO2012113948A1 WO 2012113948 A1 WO2012113948 A1 WO 2012113948A1 ES 2012000039 W ES2012000039 W ES 2012000039W WO 2012113948 A1 WO2012113948 A1 WO 2012113948A1
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Agustín RUIZ LAZA
Mario EZQUERRA TRABALÓN
Antonio GONZÁLEZ PÉREZ
Javier GAYÁN GUARDIOLA
Francisco Jesús MORÓN CIVANTOS
José Miguel CARRASCO CALANCHA
Luis Miguel REAL NAVARRETE
Eduardo TOLOSA SARRÓ
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Fundacion Alzheimur
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Fundacion Alzheimur
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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
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention is part of the procedures to aid in the diagnosis of complex diseases. Specifically, the present invention pertains to procedures based on genetic markers indicative of the predisposition of a subject to suffer from Parkinson's disease. More specifically, the procedure, in Vitro, focuses on the detection, individually or jointly, of SNPs in various genes for the prognosis of said predisposition, based on the genome of an individual.
  • Parkinson's disease is a neurodegenerative disorder of the central nervous system that is often disabling from a motor point of view, also affecting speech and other neurological functions.
  • PD affects 1% of the population at 50 years and 4% of the population at 85 years (1).
  • PD belongs to a group of disorders called “movement” and is characterized by the presence of muscle stiffness, tremor, slowness of movement (bradykinesia) and even complete loss of movement (aciniesia) in cases more extremes
  • the symptoms observed are results of a decrease in the stimulation of the motor cerebral cortex from the basal ganglia. Secondary symptoms may include cognitive disorders and language disorders.
  • the course of the disease is chronic and progressive.
  • PD phenocopies PD (individual or group of individuals in a population which lack a given genotype has the same phenotype (PD) than that which if it possesses said genotype) due to intoxications and infections of the central nervous system should not be ruled , the bulk of PD cases are considered "complex" forms of the disease whose etiology would be due to linear and non-linear integration processes of a multitude of genetic factors (low penetrance alleles) and non-genetic (environmental factors, basically toxic or Infectious agents).
  • SNCA alpha- synuclein, NM_000345) (3), the region of MAPT (microtubule- associated tau protein, NM_001123066) (4), NUCKS1 (nuclear casein kinase and cyclin -dependent, NM_022731) (5), PM20D1 (peptidase 20 domain containing 1 precursor, BC063477) (6), SLC41A1 (solute carrier family 41 member 1, N _173854) (7), BST1 (marrow stromal cell antigen 1 precursor, NM_004334 ) (8), LRRK2 (leucine-rich repeat kinase 2, NM_198578) (9), USP24 (ubiquitin specific protease 24, N _015306) (10), SLC6A3 (solute carrier family 6, NM_001044) (11) and GBA (glucocerebrosidase precursor, NM_000157) (12).
  • SNCA alpha- synuclein, NM
  • oligonucleotide that detect SNPs across the entire genome capable of identifying and genotyping of 10,000 or more SNPs in each individual, may reveal which SNPs are present or absent in patients and in controls of a specific genetic association study.
  • the data generated in these studies can be conceptualized as a table of values in which each column represents an individual genome, each line a certain SNP in said genomes, with a + or - symbol in each cell representing the presence or absence of the said SNP in each genome investigated.
  • HFCC computer application (WO2008010195) allows to determine genetic associations and identify genes that influence the appearance of any phenotypic trait, individually or jointly. This application allows you to filter, delete and select those associations that will be validated later in larger groups.
  • PINK1 PTEN induced putative kinase 1 precursor, NM_032409
  • HtrA2 HtrA serine peptidase 2 isoform 1 preproprotein, NM_013247
  • the present invention provides new methods for predicting, preclinically, the susceptibility to suffer PD of complex etiology, by employing new genetic markers (Single Nucleotide Polymorphisms, SNPs) or combinations thereof.
  • SNPs Single Nucleotide Polymorphisms
  • the present invention provides a new method of genetic scoring, based on the specific genotype of the loci of said genetic markers and others associated with the age of onset of the disease, which allows the classification of individuals in patients affected by complex PD No need for additional factors. Brief description of the figures.
  • Figure 1 Graphical representation by means of a Forest plot of the effect of the TT / CT diploma of the markers rs869026 and rsl0945364 in Parkinson's disease. Pooled: joint effect of the three series.
  • Y Relative Risk;
  • the inventors used the bioinformatic technology of HFCC meta-analysis (Hypothesis Free Clinical Cloning, WO2008010195) to select combinations of genetic markers distributed throughout the genome that are associated with Parkinson's disease.
  • stage I a complete genome scan was performed with HFCC applied to 272 cases and 272 controls.
  • the best couples made up of 384 independent markers were evaluated in the Spanish and North American population (Stage II and III). Only those couples who show a consistent effect on the three Studies undergo a meta-analysis (a study based on the structured and systematic integration of information obtained in different clinical studies, on a particular health problem, consisting of identifying and reviewing controlled studies on a certain problem, in order to give a synthetic quantitative estimate of all available studies.) (stage IV).
  • the term "genetic marker” and its plural refers to single nucleotide change polymorphisms (SNPs), from now on they will also be referred to as markers of the invention or SNPs of the invention interchangeably.
  • SNPs single nucleotide change polymorphisms
  • the present invention uses the meta-analysis of three independent series of cases of complex PD and unrelated controls. Two of the series are North American and were obtained from the public repositories of the National Center for Biotechnological Research (NCBI). The remaining series is Spanish and was obtained thanks to a collaboration with the Hospital Clinic of Barcelona. In total, the genotypes obtained from the DNA of 2697 independent individuals (1305 cases of complex PD and 1391 controls) were used for this study.
  • HFCC technology can be applied to select a set of diplomatic genetic markers (genotype combinations of two independent SNPs) to explain the differential risk that individuals have to suffer from PD.
  • markers although selected in pairs, retain the degree of association individually, so they can be used both individually, as in pairs, or together.
  • the public data of complete genomes can be used.
  • the repositories that guard said data will have been responsible for genotyping the samples of the individuals.
  • HFCC technology is applied through the use of solid devices or supports containing oligonucleotides capable of hybridizing with known SNPs. These devices are known in the art as SNPs or SNP Arrays chips and are commercially available. Using these starting materials, the genome of the selected individuals can be explored to identify all possible diplomotypic combinations. The appropriate filters are selected in the HFCC application.
  • HFCC systematically uses three filters in different phases of the study: a noise filter, which is a control-control comparison to eliminate spurious associations due to bad randomization of the diploma in the control group, an address filter that selects only those combinations in the that the direction of the effect is concordant and a filter tractor alleles (tracking ally filter) that identifies strongly deviated markers that introduce false positives.
  • the desired statistical parameters are included, for which the HFCC has a parallel computing algorithm. The selection of the desired markers is carried out automatically and subsequently, these SNPs are ordered and prioritized using either suitable software for this purpose or through conditional analysis strategies based on genes previously associated with PD. In this way, the best pairs of SNPs can be selected to design a validation test, which is carried out in series independent to purify the selection, eliminate false positives and retain the SNPs consistently associated with PD.
  • the gene sequences to be synthesized for the multiple genotyping assay are determined. These sequences must be suitable for simultaneous reading in the BeadXpress System.
  • the BeadXpress (I Ilumina inc, USA) technology consists of a 30nm resolution two-channel simultaneous non-confocal laser reader that allows you to read the holographic cylinders used in Veracode technology (I Ilumina inc, USA) (see below).
  • SNPs of the invention can be genotyped by an isolated sample of an individual, by contacting probes for SNPs with genomic DNA isolated from said sample, under appropriate conditions for hybridization of said probe to said gene.
  • Said probe can be a wild-type DNA (that is, the SNP under investigation is not present in the probe, and hybridization takes place when the SNP according to the invention is not found in the DNA in the sample), or a mutant (that is, transporting the SNP that is sought, and hybridization only takes place if the SNP is found in the DNA in the sample).
  • sample is understood as a portion of tissue or volume of body fluid, preferably peripheral blood, but which can also be any other tissue isolated from the body, for example by biopsy, or fluid sample body that contains the DNA of the individual under study.
  • tissue or volume of body fluid preferably peripheral blood
  • sample body that contains the DNA of the individual under study.
  • allelic probes to be used, their lengths, preferably between 50-300 bases, or the hybridization conditions. Sequences that flank the SNP can be used and that the expert will find in the sequence listing of the present invention.
  • Veracode is the technology of choice for the validation of HFCC results. This technology uses the power of digital holographic code to offer a robust detection system and is ideal for multiple tests that require high accuracy, reproducibility and speed.
  • the system uses microspheres differentiated by a holographic mark of high density (24-bit). When the VeraCode microspheres are excited by a laser, each one emits a unique image code, which allows a quick and specific detection by the reading system called "BeadXpress Reader System” (Illumina inc, USA). According to the level of multiplex required, the tests are created by mixing different microspheres (cylinders) with different codes, which can range from one to several hundred.
  • Each type of micro-sphere carries on the surface covalently bound oligonucleotide species specific to the region containing the polymorphism. Previously, said region is detected in each of the genomes to be studied using the Illumina GoldenGate system (Illumina Inc, USA). In this way, the system can simultaneously interrogate up to 384 single nucleotide polymorphisms (SNPs) per DNA sample.
  • the Goldengate system allows the genotyping of SNPs through a process of extension and ligation of "sequence-specific" DNA. The system allows to link only those oligos hybridized correctly. The correct fragments, once bound, are amplified with universal primers. At - * t - - - - - - -
  • a first object of the present invention is an in vitro method for determining the predisposition to suffer from Parkinson's disease in an isolated sample of an individual, comprising genotypic analysis of at least one SNP to be chosen from the group consisting of : rs577562, rs2986574, rsllll9097, rs4658673, rs4490160, rsl0496075, rsl2987286, rs847126, rs9036, rs6805546, rs4505714, rs7650598, rsl0155062, rs218280, rs869026, rs3094694, rsl549355, rs7747934, rs4583999, rsl0945
  • Table 2 shows the chromosomal location, the name of the gene and the access number of the SNPs of the invention while in Table 1 the relationship between the SNPs of the invention, the variation they present, and the sequence list are shown. of the invention, which include the flanking nucleotide sequences.
  • the in vitro method of the invention is useful for predicting the risk of complex PD from an isolated sample of an individual.
  • the in vitro method of the invention uses the SNPs rs869026 and rsl0945364, located on chromosomes 5 and 6 respectively.
  • SNPs rs869026 and rsl0945364 located on chromosomes 5 and 6 respectively.
  • Another aspect of the present invention provides an in vitro method for determining the predisposition to suffer from Parkinson's disease in an isolated sample of an individual, which comprises the genotypic analysis of at least one SNP to choose from the group consisting of: rsl039189, rsl2987286, rsl364658, rsl549355, rs218280, rs2332631, rs353111, rs394475169, rs3957751606 , rs761267, rs7650598, rs869026 and their combinations.
  • SNPs markers
  • a panel of markers SNPs
  • predictive capacity For the construction of said panel, a combination of SNPs associated with the "status" of cases is used (these are the markers present in Table 5) to which is also added a small subset of markers that present statistically significant indications of association with the age of onset of the disease ( ⁇ . ⁇ , age-at-onset) (Table 6).
  • Example 4 shows the creation of said predictive panel, which can be used as a genetic scoring system based on the genotypes of the loci, which allows the classification of affected individuals of complex PD without having to take into account any other factor.
  • of the present invention is an in vitro method based on a genetic scoring system comprising the joint genotypic analysis of the SNPs: rs577562, rs2986574, rsllll9097, rs4658673, rs4490160, rsl0496075, rsl2987126 , rs9036, rs6805546, rs4505714, rs7650598, rsl0155062, rs218280, rs869026, rs3094694, rsl549355, rs7747934, rs4583999, rsl0945364, rsll56143, rsl888349, rsl2353255, rs7027515, rs332185, rs763373, rsl0750861, rsll564173, rs2332631, rsl039189
  • a set of reagents or kit for the determination of the predisposition to suffer from parkinson's disease in an isolated sample of an individual, characterized is also the subject of the present invention.
  • the 541 available individuals were genotyped for 396,591 different SNPs distributed in the 22 autosomes. To do this they used two chips (SNP arrays Infinium I and II) of the Illumina company (Illumina Inc, USA). With this starting data, HFCC technology was used to explore all possible diplomotypic combinations of the 396,591 genotyped SNPs markers. As a result, an exhaustive screening of all existing civil patterns was carried out. In this way, the database available is divided into three replication groups of 90 cases and 90 controls (one of them had one more control) and the HFCC software was executed programming the statistical evaluation of all the diplomas (2-loci models M1, M2 and Mi 6 according to Li and Reich 2000 (7)).
  • the system selected 4.4% of the markers (17825 SNPs) that formed 26371 diploma combinations. These were ordered and prioritized using either Alambique software (21) or conditional analysis strategies (looking for pairs of markers that at least contained SNPs within genes previously associated with PD). The 384 most promising selected SNPs (table 2) were correspondingly validated in independent series (see below).
  • SNPs selected by HFCC Sense or forward chain data.
  • CV validation class
  • BV Validation tray
  • LGR Location Relating to Gen.
  • OPA Oligonucleotide Pooling Assay
  • the panel of markers selected during HFCC was sent to the company IIlumina Inc to perform a bioinformatic analysis and determine the gene sequences that will be synthesized for the multiple genotyping assay (OPA, oligonucleotide pooling assay).
  • Chr5_rs869026 x chr6_rsl0945364 as a genetic susceptibility factor for the disease after performing a complete bi-variant complete genome scan and two validation batches.
  • stage I the HFCC
  • two independent validations were used.
  • OR Odds ratio
  • This English term has been translated as ratio of possibilities, ratio of odds, odds ratio and is the ratio of two reasons: the numerator is the reason for the probability of an event happening and the probability that it does not happen under certain conditions and the denominator is the reason for the probability that such an event will happen and the probability that it will not happen under the complementary conditions.
  • the genomic marker rsl0945364 is found in a gene desert (that region of the genome where there are no known coding sequences) of the long arm of chromosome 6 (6q27). Therefore, no hypothesis can be established about the biological plausibility of this chromosomal region with respect to Parkinson's disease since it is unknown what functions this region contains.
  • the rs869026 marker located at 5q31.2, is in the 5 'region of the SILl gene. This gene is responsible for Marinesco-Sj ógren Syndrome and is a very strong candidate for complex neurodegenerative disorders. However, it is important to indicate that, to date, this gene had never been studied or associated for Parkinson's disease.
  • PLINK a tool set for whole-genome association and population-based linkage analyzes Purcell S, Neale B, Todd-Brown K. , Thomas L, Ferreira MA, Bender D, aller J, Sklar P, from Bakker PI, Daly MJ, Sham PC. Am J Hum Genet. 2007 Sep; 81 (3): 559-75).
  • the software allows the genetic evaluation of multiple markers and the performance of different genetic tests that serve as a measure of heterogeneity.
  • SNPs must maintain their association when we calculate their effect with a logistic regression adjusted for age and sex, ii) they must support an analysis stratified by study (Stages 1,2,3) iii) there must be absence of heterogeneity (Breslow index> 0.05) and iv) the meta-analysis adjusted for age and sex must be positive.
  • Table 5 shows the SNPs markers selected by HFCC and which have been validated by analyzing two additional independent series of cases and controls using different statistical methods.
  • the markers located on chromosome 12 rslll75655, rsll564173, rsll564203, rsll829088, rsl907632, rs2723264
  • This gene has been previously involved in PD (9).
  • its inclusion in the selection made by HFCC demonstrates the efficiency of the method applied.
  • the markers identified by conventional genotyping technologies such as PCR-RFLP, ARMS, real-time PCR or direct sequencing of PCR products etc. are genotyped.
  • ORconjunta average effect of each marker taking into account the three studies carried out.
  • Table 6 is the result of this second selection of markers and provides a total of 21 SNPs of the HFCC panel that are significantly associated (p ⁇ 0.05) to the age of PD onset (AAO).
  • This calculation was carried out with plink (PLINK: a tool set for whole-genome association and population-based linkage analyses. Purcell S, Neale B, Todd-Brown K, Thomas L, Ferreira MA, Bender D, aller J, Sklar P, from Bakker PI, Daly MJ, Sham PC.Am J Hum Genet. 2007 Sep; 81 (3): 559-75) using linear regression (--linear) adjusting the effect by sex and by the series to which the patient.
  • SNP single nucleotide polymorphism.
  • CHR chromosome.
  • BP base pairs.
  • Al allele 1.
  • NMISS number of individuals available for the study.
  • BETA Beta linear regression coefficient.
  • Stat statistical value of the linear regression.
  • P significance value.
  • Table 8 shows the results of the discriminant analysis and cross-validation using the constructed function and issuing a score for each individual with the coefficients of Table 7.
  • the results demonstrate a predictive capacity of the control status of 72.8% ( cross validation 71.8%) and a predictive capacity of case status of 77.4% with a resulting cross validation of 75.7%. These estimates far exceed 50% (which is estimated to happen if it will be about predicting the condition of sick PD or healthy by throwing a coin in the air (that is by chance, table 8
  • the data obtained with the present invention indicate, therefore, that the combination of SNPs rs577562, rs2986574, rsllll9097, rs4658673, rs4490160, rsl0496075, rsl2987286, rs847126, rs9036, rs6805546, rs450575, rs5355995, rs650914, rs650914, rs6505145, rs4509145, rs4509145, rs4509146 , rs7747934, rs4583999, rsl0945364, rsll56143, rsl888349, rsl2353255, rs7027515, rs332185, rs763373, rs763373, rsl0750861, rsll564173, rs2332631, rsl0399 subset of individuals in the population at
  • the 532 controls of this validation were collected from pre-compiled panels in the Coriell repositories. All selected individuals expressed their status as Caucasian targets free of neuropsychiatric diseases and were questioned about neurological diseases such as Alzheimer's disease, amioatrophic lateral sclerosis, ataxias, autism, major depression, cerebrovascular diseases, dementia, Parkinson's disease and schizophrenia . His parents and siblings did not have neurological diseases either. The average age of these controls is 58 years (15-98 years).
  • Genotypes belonging to these individuals were extracted directly from the matrices obtained from NCBI using conventional computer technologies. Specifically, we obtained the 384 markers mentioned in table 2 by successively applying to the NCBI matrices the commands -proxy-impute all (to infer the markers that were not present), --snp (to select from the matrix the list of SNPs from interest) and -make-bed (to generate a new data matrix exclusively with the selected markers).
  • the raw genotypes obtained from the matrices were used as input for the HFCC software and other bioinformatics programs, such as PLINK, which are used to evaluate the results of the study.
  • PLINK (6) and in particular the -assoc command, allows the univariate study of each SNP with respect to the disease.
  • the -linear command allows the adjusted linear regression analysis.
  • the -logistic command allows the logistic regression analysis adjusted by age and sex, the - within and -homog commands allow the calculation of the heterogeneity index and the Breslow-Day statistic and the stratified analysis by series.
  • the --meta-analysis command allows the joint analysis of all studies.
  • HFCC is used for bi-variant analysis.
  • the plot of Forest is done with the free episheet software
  • Clark IE Dodson MW, Jiang C, Cao JH, Huh JR, Seol JH, et al. Drosophila pinkl is required for mitochondrial function and interacts genetically with parkin. Nature 2006 4 1 (7097): 1162-6.
  • BAP a mammalian BiP- associated protein, is a nucleotide exchange factor that regulates the ATPase activity of BiP. J Biol Chem. 2002; 277 (49): 7557-63.

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Abstract

La présente invention concerne un procédé pour prédire la prédisposition d'un individu à être atteint de la maladie de Parkinson (PD) à partir d'un échantillon de sang isolé dudit individu. Ledit procédé comprend l'utilisation combinée de 36 nouveaux SNP présentant une capacité pour prédire précliniquement l'apparition de PD complexe. La présente invention concerne également un procédé comprenant l'utilisation d'une combinaison digénique de SNP du loci SIL1 x chr6, qui confère à ses porteurs un risque accru d'être atteint de la maladie de Parkinson.
PCT/ES2012/000039 2011-02-25 2012-02-22 Procédé pour la détermination de la prédisposition génétique à la maladie de parkinson Ceased WO2012113948A1 (fr)

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ES201130254A ES2387358B1 (es) 2011-02-25 2011-02-25 Procedimiento para la determinación de la predisposición genética a la enfermedad de parkinson.

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Cited By (8)

* Cited by examiner, † Cited by third party
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US20140155271A1 (en) * 2011-11-04 2014-06-05 Population Diagnostics, Inc. Methods and compositions for diagnosing, prognosing, and treating neurological conditions
US11180807B2 (en) * 2011-11-04 2021-11-23 Population Bio, Inc. Methods for detecting a genetic variation in attractin-like 1 (ATRNL1) gene in subject with Parkinson's disease
US20230220468A1 (en) * 2011-11-04 2023-07-13 The Research Foundation Of State Of University Of New York Methods for detecting a genetic variation in attractin-like 1 (atrnl1) gene in subject with parkinson's disease
US11174516B2 (en) 2012-02-09 2021-11-16 The Hospital For Sick Children Methods and compositions for screening and treating developmental disorders
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US12012634B2 (en) 2012-09-14 2024-06-18 Population Bio, Inc. Methods for diagnosing, prognosing, and treating parkinson's disease or parkinsonism
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