OAS1 splice site polymorphism controlling antiviral enzyme activity influences susceptibility to type 1 diabetes

Both genetic and nongenetic factors contribute to the development of type 1 diabetes. Many investigations, including prospective studies of high-risk children, have implicated virus infections as predisposing environmental agents. We previously reported that basal activity of the key antiviral enzyme 2'5'-oligoadenylate synthetase (2'5'AS) was significantly elevated in type I diabetic patients compared with healthy control subjects. Recently, we showed that an A/G splice site single nucleotide polymorphism (SNP) in the OAS1] gene encoding 2'5'AS is strongly associated with basal 2'5'AS activity. Basal enzyme activity was highest in individuals with GG genotype and lowest in those with AA genotype. In the present study, we genotyped 835 type I diabetic and 401 healthy siblings at the OAS1] splice site polymorphism and (for comparison) at an A/C SNP of the insulin (IDDM2) locus. Results showed that OAS1 GG and GA were significantly increased in diabetic compared with healthy siblings (P = 0.0023). The strength of association was similar to that at IDDM2, where, as expected, the C/C (variable number tandem repeat class I homozygote) genotype was increased in affected compared with healthy siblings (P = 0.0025). The results suggest that host genetic response to virus infection could influence susceptibility to type I diabetes.