OAS1 gene haplotype confers susceptibility to multiple sclerosis

Abstract

Multiple sclerosis (MS) is associated with genetic susceptibility and unknown environmental triggers, possible viral infections, but the specific etiological mechanism that subsequently develops into an inflammatory/autoimmune cascade of events is poorly understood. Recently, genetic variants of 2',5'- oligoadenylate synthetase 1 (OAS1) gene, a critical enzyme involved in innate antivirus response, have been associated with differential enzyme activity and type 1 diabetes in both case-control and family studies. We hypothesized that polymorphisms in the OAS1 gene could influence the susceptibility to MS. To test this hypothesis, we conducted a case-control study of 333 patients with MS and 424 healthy controls and genotyped two OAS1 single nucleotide polymorphisms (SNPs) by restriction fragment length polymorphism method: rs 10774671, A/G SNP altering the splicing site at the seventh exon, and rs 3741981, a nonsynonymous (Ser162Gly) A/G SNP in the third exon. Haplotype but not single-marker analysis revealed an association of the haplotype created by the G allele at rs 10774671 and the A allele at rs 3741981 with the susceptibility to MS (P value = 8.8 x 10(-5)). Subjects carrying this haplotype had an increased risk of MS comparing with those not carrying it (odds ratio = 4.7, 95% confidence interval 2.1-10.9). Our findings indicate that the OAS1 gene polymorphisms may confer susceptibility to MS or serve as markers of functional variants and suggest that OAS1 activity is involved in the etiology of the disease. Future studies in a larger sample and association analysis with functional variants will clarify the role of the OAS1 gene in the susceptibility to MS.

Common polymorphic transcript variation in human disease

“…The most significant probe set can hybridize only to the extended transcript variant and can thus differentiate between them; as shown in Figure 2A, not a single CEPH individual overlaps in expression level of this probe set between genotypes (P < 10 À89 ). OAS1 is an enzyme involved in innate antiviral response with splice variants that are known to affect susceptibility to viral infection (Bonnevie-Nielsen et al 2005) and multiple sclerosis (Fedetz et al 2006). The same splice site SNP known to associate with disease susceptibility was recently shown also to associate with splicing of OAS1 in CEPH cell lines (Kwan et al 2007), a finding that is confirmed by our analysis (Supplemental Fig.…”

“…Two of these (IRF5 and OAS1), the two top hits genome-wide ( Fig. 2A,B; Table 1), have already been convincingly associated with both polymorphic splicing and other autoimmune diseases (Fedetz et al 2006;Graham et al 2007;Kozyrev et al 2007), so their unreplicated associations with RA and CD are quite plausible (and previous work supports the IRF5-RA association as well) ). For the four replicated disease SNPs, we implicate four genes that are all good functional candidates: ERAP1, PTPN2, CLEC2D, and TRAF1.…”

“…(Graham et al 2007;Kozyrev et al 2007). b OAS1 splice variants have also been associated with multiple sclerosis (Fedetz et al 2006) and viral infectivity (Bonnevie-Nielsen et al 2005).…”

“…Much more challenging has been connecting common genetic variation affecting PTV to complex multigenic diseases, in large part because of the less pronounced effects such variants may have on both splicing and disease. Nevertheless, several examples of associations between common variants affecting both PTV and disease risk have been reported, including splicing of IRF5, OAS1, CTLA4, and PTPRC (formerly known as CD45) in several autoimmune diseases (Lynch and Weiss 2001;Ueda et al 2003;Fedetz et al 2006;Graham et al 2007;Kozyrev et al 2007), and NPSR1 (also known as GPRA) in asthma (Laitinen et al 2004). These examples, while few in number, suggest that a systematic study of PTV may reveal more cases like these.…”

Alternative splicing in multiple sclerosis and other autoimmune diseases

“…Thus, EAE-susceptible mice are prone to developing the site of exon 7 and the "A" allele of a SNP in exon 3, has been linked to increased OAS1 enzyme activity as well as MS and type 1 diabetes susceptibility. [68][69][70][71] Importantly, different alternatively spliced mRNA isoforms are produced depending on which allele is present at the 3' splice site of exon 7. 69 However, functional data establishing the role of these alternative splicing products and their corresponding protein counterparts in susceptibility to MS are lacking.…”