No Evidence for Association of OAS1 With Type 1 Diabetes in Unaffected Siblings or Type 1 Diabetic Cases

Abstract

Type 1 diabetes is a common autoimmune disorder that is strongly clustered in families. As the sharing of alleles of the HLA class II genes cannot explain all of this aggregation, alleles of multiple other loci are involved. Recently, it was reported that an A/G splice-site single nucleotide polymorphism (SNP; rs10774671) in the OAS1 gene, encoding 25-oligoadenylate synthetase, was associated with a protective effect against type 1 diabetes in unaffected siblings, and yet affected siblings showed random transmission. Since this finding is difficult to explain biologically, we genotyped the OAS1 SNP in 1,552 type 1 diabetic families from the U.K., U.S., Romania, and Norway and in 4,287 type 1 diabetic cases and 4,735 control subjects from the U.K. We found no evidence of association in either unaffected (relative risk 1.00; P ‫؍‬ 0.94) or affected (1.00; P ‫؍‬ 0.96) siblings or in the case-control study (odds ratio 0.99; P ‫؍‬ 0.83). These results suggest that additional evidence of association of a low penetrance effect in common disease should be sought when the primary result comes from unaffected siblings in the absence of any effect in cases. Diabetes 55: [1525][1526][1527][1528] 2006

Alternative splicing in multiple sclerosis and other autoimmune diseases

“…Caution, however, needs to be taken when assessing the contribution of individual OAS1 SNPs to the development of MS and other autoimmune diseases, due to the longrange linkage disequilibrium between OAS1 polymorphisms, 68,71 as well as recently reported inconsistencies in association of OAS1 with type 1 diabetes. 72,73 KLC1. One report suggests a possible involvement of a particular variant of the kinesin light-chain 1 (KLC1) gene in protection against MS. 74 Kinesin is involved in trafficking of the myelin synthesis apparatus 74,75 (hence a direct connection to MS), and a protective SNP within intron 13 of the KLC1 gene has been hypothesized to affect splicing.…”

Mitochondrial localization of the OAS1 p46 isoform associated with a common single nucleotide polymorphism

“…The rs1131454 SNP (former rs3741981) is an A or G positioned in exon 3 resulting in an OAS1 protein with either Ser162 or Gly162 in the core domain. The association between these two SNPs and Type 1 diabetes has not been confirmed in a larger study, though others have concluded that there may be a very weak association between the rs1131454 (former rs3741981) and rs10774671 SNPs and Type 1 diabetes in a population of European descents, however these authors stated that this association might also be linked to other SNPs in the OAS1 locus [16,17]. In multiple sclerosis the same haplotype was studied in a Spanish study group [18].…”

Reassessment of the type I diabetes association of the OAS1 locus

“…The three reported OAS1 SNPs were not genotyped in the Wellcome Trust Case–Control Consortium; however, SNP rs2660 has r 2 = 1 with rs10774671 (Supplementary Table 1). The genotypic association was not replicated, however, in the 1552 T1D families and 4287 T1D cases vs 4735 controls from the same population 7. Thus, the possible genotypic association still lacks statistical validation.…”

“…Although methodological limitations of that study were later identified,7 in our independent study on candidate polymorphisms, the highly correlated ( r 2 = 0.69) non-synonymous (Ser162Gly) SNP rs3741981 of the OAS1 gene was significantly associated with T1D risk 8. In two large cohorts of European descent, however, no statistically significant association of OAS1 SNPs with T1D was observed 7…”