WO2010094525A1 - Marqueurs génétiques pour le diagnostic de formes progressives primaires de la sclérose en plaques - Google Patents

Marqueurs génétiques pour le diagnostic de formes progressives primaires de la sclérose en plaques Download PDF

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WO2010094525A1
WO2010094525A1 PCT/EP2010/050378 EP2010050378W WO2010094525A1 WO 2010094525 A1 WO2010094525 A1 WO 2010094525A1 EP 2010050378 W EP2010050378 W EP 2010050378W WO 2010094525 A1 WO2010094525 A1 WO 2010094525A1
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snps
multiple sclerosis
individual
primary progressive
progressive forms
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PCT/EP2010/050378
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Hadi Abderrahim
Jérôme Wojcik
Federica Esposito
Giancarlo Comi
Filippo Martinelli Boneschi
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Merck Serono S.A.
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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
    • C12Q2600/112—Disease subtyping, staging or classification
    • 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 use of SNPs to identify an association with primary progressive forms of Multiple Sclerosis (MS) for diagnostics.
  • MS Multiple Sclerosis
  • MS Multiple Sclerosis
  • CNS Central Nervous System
  • MS is extremely heterogeneous from a clinical and histopathological point of view 8 , and neurological sequelae of the disease are determined 0 by a variable mixture of demyelination, axonal loss and neuronal death in the CNS.
  • onset of the disease is characterized by sudden exacerbations followed by a complete or partial recovery (relapsing-remitting, RR), which are the clinical counterpart of bursts of inflammatory phenomena with rupture of the blood-brain barrier and new white matter lesions formation.
  • both PPMS and RRMS are associated with the DR2 haplotype DRB1 * 1501 in the class Il region of the MHC on chromosome 6 11 "14 , suggesting no genetic difference, but a large study on more than 1 ,000 families with > 2 first-degree relatives pointed out that MS affected siblings tend to share the same disease course (RR vs PP) more often than expected by chance (kappa 0.12; p ⁇ 0.001 ) 15 .
  • MS variants named progressive-relapsing 16 and single attack progressive 17 according to previous definitions, represent variants of the PP phenotype.
  • markers in particular genetic markers, useful in MS patients.
  • genetic markers useful in association with primary progressive forms of MS in particular there exists a need to identify genetic markers useful in association with primary progressive forms of MS.
  • the invention relates to a method for genotyping comprising the steps of isolating a nucleic acid from a sample of an individual; and determining the type of nucleotide in rs6956703, rs1 1767658, rs1 1748246, rs164151 , rs9868633, rs9868869 and/or rs9813102 in the biallelic marker, and /or in a SNP in Linkage Disequilibrium (LD) with one or more of these SNPs, and/or one or more SNP in LD with either of DPP6, NRG2, NRG1 , NRG3, NRG4, NOSIAP, GPR160, CCDC39, EYA2.
  • LD Linkage Disequilibrium
  • the invention relates to correlating the result of the genotyping steps with a risk of suffering or a predisposition for primary progressive forms of Multiple Sclerosis (MS).
  • MS Multiple Sclerosis
  • the invention relates to a method for genotyping comprising the steps of isolating a nucleic acid from a sample of an individual; and determining the type of nucleotide in rs6956703, rs1 1767658, rs11748246, rs164151 , rs9868633, rs9868869 and/or rs9813102 in the biallelic marker, and /or in a SNP in Linkage Disequilibrium (LD) with one or more of these SNPs, and/or one or more SNP in LD with either of DPP6, NRG2, NRG1 , NRG3, NRG4, NOSIAP, GPR160, CCDC39, EYA2, wherein said method further comprises the step of correlating the result of the genotyping steps with a risk of suffering or a predisposition for primary progressive forms of Multiple Sclerosis.
  • LD Linkage Disequilibrium
  • the invention relates to the use of one or more SNPs selected from the group consisting of rs6956703, rs1 1767658, rs1 1748246, rs164151 , rs9868633, rs9868869, rs9813102, SNPs in Linkage Disequilibrium (LD) with one or more of these SNPs, and one or more SNPs in LD with either of DPP6, NRG2, NRG1 , NRG3, NRG4, NOSIAP, GPR160, CCDC39, EYA2 for predicting a risk of suffering from or a predisposition for primary progressive forms of Multiple Sclerosis (PPMS).
  • LD Linkage Disequilibrium
  • the invention in yet another aspect relates to a method for predicting a risk of suffering from or a predisposition for primary progressive forms of Multiple Sclerosis in an individual comprising a) extracting the nucleic acid from a sample of said individual; b) identifying the presence of a useful genetic marker in said individual by known methods; c) based on the results of step b) making a prediction of the probability as to the development of primary progressive forms of Multiple Sclerosis for said individual.
  • the invention relates to the treatment of primary progressive forms of Multiple Sclerosis (PPMS) by applying the methods according to the invention and treating the identified PPMS patients with an interferon-beta.
  • PPMS primary progressive forms of Multiple Sclerosis
  • Table 3 HLA-DRB15 positivity across several samples: a sample of Italian PPMS cases, a sample of Italian RR/SP MS, a sample of Nordic countries MS patients, and a sample of MS patients of French origin.
  • Figure 1 Marker density, association results, allelic and genotypic p values, and linkage disequilibrium structure for the locus that contains the DPP6 gene. Top: marker density and location of the SNPs in the locus that contains the DPP6 gene. Middle: negative logarithm of allelic and genotypic p values of 10 SNPs around the two associated SNPs (rs6956703 and rs1 1767658) in the region. Bottom: linkage disequilibrium pattern between SNPs.
  • Figure 2 Concordance between Affymetrix and TaqMan methodologies. Negative logarithm of p values of best hit SNPs according to two different methodologies: Affymetrix and TaqMan. The red cross-line represents the perfect intersection of concordance.
  • the present invention in one aspect is directed to a method for genotyping comprising the steps of a. isolating a nucleic acid from a sample of an individual; and b. determining the type of nucleotide in rs6956703, rs1 1767658, rs1 1748246, rs164151 , rs9868633, rs9868869 and/or rs9813102 in the biallelic marker, and /or in a SNP in Linkage Disequilibrium (LD) with one or more of these SNPs, and/or one or more SNP in LD with either of DPP6, NRG2, NRG1 , NRG3, NRG4, NOSIAP, GPR160, CCDC39, EYA2.
  • LD Linkage Disequilibrium
  • the identity of the nucleotides at said biallelic markers is determined for both copies of said biallelic markers present in said individual's genome. Any method known to the skilled person may be applied, preferably said determining is performed by a microsequencing assay. Furthermore, it is possible to amplify a portion of a sequence comprising the biallelic marker prior to said determining step, e.g. by PCR. However, any applicable method can be used.
  • the method further comprises the step of correlating the result of the genotyping steps with a risk of suffering or a predisposition for primary progressive forms of Multiple Sclerosis.
  • the inventors thus advantageously provide for a means to differentiate between different patient groups of the overall MS population. This is not only positive to more precisely classify Multiple Sclerosis patients and make a better prediction with respect to the disease development.
  • the invention hence provides also for a tool that has implications for handling such patinets better according to the particular needs of this Multiple Sclerosis disease form. Moreover, it will have positive implications for the patients' psychological, social and medical treatment.
  • the invention relates to one or more SNPs selected from the group consisting of rs6956703, rs1 1767658, rs1 1748246, rs164151 , rs9868633, rs9868869, rs9813102, SNPs in Linkage Disequilibrium (LD) with one or more of these SNPs, and one or more SNPs in LD with either of DPP6, NRG2, NRG1 , NRG3, NRG4, NOSIAP, GPR160, CCDC39, EYA2 for use to predicting a risk of suffering from or a predisposition for primary progressive forms of Multiple Sclerosis.
  • SNPs selected from the group consisting of rs6956703, rs1 1767658, rs1 1748246, rs164151 , rs9868633, rs9868869, rs9813102, SNPs in Linkage Disequilibrium (LD) with one or more of these
  • the invention is directed to a method for predicting a risk of suffering from or a predisposition for primary progressive forms of Multiple Sclerosis in an individual comprising a. extracting the nucleic acid from a sample of said individual; b. identifying the presence of a useful genetic marker in said individual by known methods; c. based on the results of step b) making a prediction of the probability as to the development of primary progressive forms of Multiple Sclerosis for said individual.
  • the genetic marker is one or more SNPs selected from the group consisting of rs6956703, rs1 1767658, rs1 1748246, rs164151 , rs9868633, rs9868869, rs9813102, SNPs in Linkage Disequilibrium (LD) with one or more of these SNPs, and one or more SNPs in LD with either of DPP6, NRG2, NRG1 , NRG3, NRG4, NOSIAP, GPR160, CCDC39, EYA2.
  • the invention relates to a method for treating primary progressive forms of Multiple Sclerosis in an individual in need thereof, the method comprising the steps of a.
  • interferon-beta is interferon-beta 1 a or 1 b.
  • interferon-beta are Rebif ® , Avonex ® , Cinnovex ® , Betaseron ® or Extavia ® .
  • the invention thus provides for a means to group Multiple Sclerosis patients and tailor and stratify the treatment approach specifically to the particular Multiple Sclerosis patient group.
  • the invention helps to adapt a specific treatment scheme according to the need of the patient. Moreover, in this manner the success rate of treatment can be positively influenced. Finally, the invention serves to more economically supply the medical resources to the particular patient according to his or her needs. This will safe in addition human and financial resource.
  • the inventors succeeded in the invention by applying an whole-genome association study performed in 197 patients selected as being affected by progressive forms of multiple sclerosis within a multicentric Italian cross-sectional study.
  • Sample size was powered to identify relatively frequent alleles with a presumed moderate-to- large effect size (OR > 2.3), while it was underpowered to identify rare and low-effect size variants.
  • the poor chance to identify rare variants is a common drawback of WGA association studies 32 , while the relatively low sample size in the study is due to the rarity of the disease course, progressive MS having a prevalence of about 10-15 cases per 100,000 inhabitants.
  • the individual allelic risk provided by the selected "best hits" was moderate-high with odds ratios ranging from 0.48 (0.32-0.71 ) to 0.60 (0.46-0.78) and from 1 .31 (0.92-1 .88). to 2.24 (1 .53-2.29).
  • the inventors could confirm an association between MS progressive forms and the HLA region in accordance with previous studies 11"14 .
  • the coded protein acts as an associated component of subthreshold-activating somatodendritic A-type K + channels 33 , which are presumed to play a fundamental role by regulating the propagation of action potential and the firing frequency in neurons 34 , thereby influencing neuronal signalling and plasticity.
  • DPP6 gene expression was significantly altered in spinal cord injury 35 , and it has been found to be associated with sporadic SLE in a WGA study 36 . It is intriguing to speculate the two disorders, PPMS and SLE, being driven by neurodegenerative phenomena in the brain and spinal cord, albeit in the absence of any known familial aggregation between the two disorders.
  • NRG2 Neuregulin 2
  • This gene belongs to the members of the NRG family, including also NRG1, NRG3, NRG4, which are involved in the differentiation and proliferation of glial cells 37 , the expression of numerous neuronal neurotransmitter receptors and synaptic plasticity 38 . It has been recently reported that NRG1 expression is dramatically reduced in active and chronic active MS lesions, inferring that the absence of neuregulin in MS lesions may contribute to the paucity of remyelination in MS 39 and that such class of genes could be exploited as potential therapeutic targets in MS.
  • NOS1AP An additional SNP, rs164151 located in the 3' region of NOS1AP.
  • NOS1AP is very enriched in the brain and has numerous colocalizations with the neuronal nitric oxide synthase (nNOS) 40 , which is known to be neuro-toxic and stimulated in the glutamatergic-Ca-mediated pathway.
  • nNOS neuronal nitric oxide synthase
  • rs9868633, rs9868869 and rs9813102 are located upstream the GPR160 gene, showing high LD between each other.
  • the gene belongs to the G-protein coupled receptor 1 family, which is presumed to be involved in transmembrane signaling in the nervous system.
  • Cases were age- and sex-matched with 234 unaffected controls defined as individuals without an history of MS and other autoimmune disorders (type I diabetes, systemic lupus erythematosus, rheumatoid arthritis, autoimmune thyroiditis, psoriasis) in any first-degree relative (Table 1 ).
  • the control and case cohorts were drawn from the same ethnic origin.
  • a semi-structured questionnaire was developed and validated to collect retrospective information about demographic (age, gender and parents' geographical origin), disease-related (age of onset, disease course, level of disability measured by Expanded Disability Status Scale (EDSS) score 20 , previous and ongoing disease-modifying treatment) and familial aggregation data (occurrence of MS or other autoimmune diseases in first-degree relatives of the probands).
  • EDSS Expanded Disability Status Scale
  • familial aggregation data occurrence of MS or other autoimmune diseases in first-degree relatives of the probands.
  • Genomic DNA was extracted from heparinized peripheral blood using a modified salting-out method or QiaAmp DNA Blood Maxi Kit (Qiagen Gmbh, Hilden, Germany), according to the manifacturer's protocol.
  • HLA-DRB1 * 15 alleles performing a high-resolution allele-specific PCR amplification with sequence-specific primers (Olerup SSPTM DRB1 * 15) 21 .
  • HLA-DRB1 genotypes by a combination of 16 PCR reactions, which amplified fragments corresponding to HLA-DRB1 * 1501 , * 1502, * 1503, * 1504, * 1505, * 1506, * 1507, * 1508, * 1509, * 1510, * 151 1 , * 1512, * 1513, * 1514, * 1515, * 1516, * 1517, * 1518, * 1519, along with amplicons for HLA-DRB1 * 16, DRB1 * 1309 and DRB * 1437.
  • Cycling was conducted as follows: 94 0 C for 2 minutes followed by 10 cycles of 94 0 C for 10 seconds (denaturation), 65 0 C for 60 seconds (annealing and extension), and 20 cycles of 94 0 C for 10 seconds (denaturation), 61 0 C for 50 seconds (annealing) and 72 0 C for 30 seconds (extension).
  • 94 0 C for 2 minutes followed by 10 cycles of 94 0 C for 10 seconds (denaturation), 65 0 C for 60 seconds (annealing and extension), and 20 cycles of 94 0 C for 10 seconds (denaturation), 61 0 C for 50 seconds (annealing) and 72 0 C for 30 seconds (extension).
  • We separated amplified products by electrophoresis in 2% agarose gels containing ethidium bromide and visualized them using ultraviolet transillumination.
  • Genotyping whole-genome analysis All cases and controls were assayed with the Affimetrix GeneChip® Human Mapping 500K Array Set. DNA samples were assayed according to a procedure described previously 22 . In particular, a total of 250 ng genomic DNA was digested with two restriction enzymes called Sty and Nsp and then ligated to the respective adapters before subsequent PCR amplification. All the steps mentioned above were carried on in the pre-PCR clean room. Cycling was conducted as follows: 95 0 C for 3 minutes followed by 35 cycles of 95 0 C for 20 seconds, 59 0 C for 15 seconds, and 72 0 C for 15 seconds.
  • SNPs genotypic and allelic frequencies were measured in cases and controls and the corresponding probability values (p-value) were computed using exact (non-asymptotic) and unbiased algorithms 24 .
  • SNPs from the Affymetrix array were ranked according to the p-values, with the most significant p-value corresponding to the highest.
  • Odds Ratios (OR) and upper and lower bound 95% confidence intervals (CIs) were computed for each SNP's minor allele.
  • SNP sequences were mapped onto NCBI 36 human genome assembly, and SNPs with multiple localizations were discarded. SNPs were mapped to the closest genes according to ENSEMBL 40 database 25 . Only SNPs from autosomal chromosomes have been studied in order to homogenize the analysis for DNA samples from males and females.
  • CSF positivity 160/177, 90.4%
  • a positivity of oligoclonal banding identified with isoelettrofocusing or as a Link index greater than 0.8.
  • Brain MRI was suggestive of MS in 181/193 (93.8% of patients), and in only 10.3% of patients there was an evidence of ongoing inflammatory activity in brain and in 8.9% in spinal cord.
  • the genotype call rate was greater than 95% for 460.220 (representing 92.5% of all SNPs assayed).
  • SNPs having a p value ⁇ 1 * 10 "4 according to allelic and/or genotypic relative frequencies were prioritized. Eighteen SNPs have been selected for the allelic p value, 10 for the genotypic p value and 8 for both, leading to a total of 20 selected SNPs ("best hits"). Sixteen of them fall within coding region of genes, defined as intronic or exonic regions of the gene or 10 kb upstream or downstream the gene, and 4 into intergenic regions called “desert regions” (Table 2). Fourteen SNPs were isolated, 3 clustered in a unique genomic region (upstream of the GPR160 gene) and 4 clustered in two genomic regions (intronic regions of DPP6 and CCDC39).
  • Figure 1 An example is provided in Figure 1 of marker density, allelic and genotypic p values, and LD structure for the locus that contains the DPP6 gene.
  • subgroup analyses have been performed on PP cases by excluding PR and SAPs courses. No SNPs yield p values more extreme than 10 "4 , and those SNPs which were defined as best hits fall within the 1 % top ranking, suggesting that genetic heterogeneity is low across PP, PR and SAPs disease courses.
  • the multiple sclerosis- and narcolepsy- associated HLA class Il haplotype includes the DRB5 * 0101 allele. Tissue Antigens 1995;46:333-6.
  • Neuregulin an oligodendrocyte growth factor absent in active multiple sclerosis lesions.
  • Jaffrey SR Snowman AM, Eliasson MJ, Cohen NA, et al.
  • CAPON a protein associated with neuronal nitric oxide synthase that regulates its interactions with PSD95. Neuron 1998;20:1 15-24.

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Abstract

La présente invention concerne l'utilisation des SNP (Single Nucleotide polymorphisms ou polymorphismes d'une seule paire de bases) dans la sclérose en plaques.
PCT/EP2010/050378 2009-01-16 2010-01-14 Marqueurs génétiques pour le diagnostic de formes progressives primaires de la sclérose en plaques WO2010094525A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2917733A4 (fr) * 2012-11-06 2016-10-19 Lineagen Inc Procédés et compositions pour le diagnostic d'une sclérose en plaques

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WO2005108997A1 (fr) * 2004-05-11 2005-11-17 Bayer Healthcare Ag Diagnostic et therapeutique de maladies associees a la dipeptidyl-peptidase 6 (dpp6)
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EP2917733A4 (fr) * 2012-11-06 2016-10-19 Lineagen Inc Procédés et compositions pour le diagnostic d'une sclérose en plaques

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