Linkage and association with the NOS2A locus on chromosome 17q11 in multiple sclerosis

Abstract

A large body of research supports a multifactorial cause in multiple sclerosis (MS), with an underlying genetic susceptibility likely acting in concert with undefined environmental exposures. Here, we used a highly efficient multilocus genotyping assay to study single nucleotide polymorphisms representing variation in 34 genes from inflammatory pathways in a well-characterized MS familial data set. Evidence of transmission distortion was present for several polymorphisms. Results for the NOS2A locus (exon 10 C/T, D346D) on chromosome 17q11 remained significant after correction for multiple testing and were reproduced in a second independent African American MS data set. In addition, linkage to a NOS2A promoter region polymorphism, (CCTTT)(n), was present in a third data set of multicase MS families. Our results provide strong evidence for linkage and association to a new candidate disease gene on chromosome 17q11 in MS and suggest that variation within NOS2A or a nearby locus contributes to disease susceptibility.

Genetic variation in nitric oxide synthase 2A (NOS2A) and risk for multiple sclerosis

“…Finally, given the importance of DRB1*15 in MS, we stratified families based on carrier status of this risk allele for analyses of all NOS2A SNPs and haplotypes to look for differences. Previous results suggested NOS2A associations were more prominent in DRB1*15-positive MS cases 20,21 and/or families, however the current study does not confirm this finding.…”

“…When analyses were stratified by carrier status of the MS-associated DRB1*15 allele in cases ( Figure 3, Supplementary Tables S3 and S4), or when 'mild' and 'severe' MS clinical outcomes were considered separately (Supplementary Table S5), differences in NOS2A allele, genotype or haplotype distributions were not observed. The previously associated NOS2A SNP (rs1137933, exon 10 D346D C/T) 20 was not replicated when the UK families were considered separately (928 trios; 301 T:316 NT, P ¼ 0.54, data not shown). All SNPs (rs no.)…”

“…A total of 427 US families from the original study were included. 20 The diagnostic criteria, ascertainment protocols and clinical and demographic characteristics of these populations are described in more detail elsewhere. 31,32,36,45 The EDSS 46 was used in conjunction with disease duration to define very mild or severe forms of MS as a secondary phenotype for analysis, as previously described.…”

“…We previously reported a NOS2A exon 10 single-nucleotide polymorphism (SNP, C/T, D346D) being associated with disease susceptibility in two independent MS datasets. 20 Evidence for excess transmission of the T allele remained significant even after correction for multiple testing in HLA-DRB1*15-positive families. Because the associated SNP confers a synonymous coding change, and other smaller NOS2A studies in MS have either suggested trends 21,22 or failed to detect an association, [23][24][25] much larger studies are needed to confidently confirm or exclude a role for this important locus in disease susceptibility.…”

Allelic association of sequence variants in the herpes virus entry mediator-B gene (PVRL2) with the severity of multiple sclerosis

“…Diagnostic criteria and ascertainment protocols have been summarized elsewhere. [48][49][50] Positive family histories were investigated by direct contact with other family members, requests for medical records, and by clinical examination, laboratory testing or paraclinical studies (MRI scanning and evoked-response testing). All affected family members were examined or had their medical records reviewed by one of the authors (SLH).…”