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 1 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 1 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 1 diabetes. Diabetes 54: 1588–1591, 2005 Type 1 diabetes is caused by some combination of multiple genetic and environmental factors that precipitate autoimmune destruction of the insulin-producing -cells of the pancreas. It is known that a preclinical period of several years often precedes development of overt diabetes, during which time autoantibodies to various -cell components appear. Although susceptibility genes in numerous regions have been suggested by linkage and association studies (1), the best documented and most widely accepted predisposing genetic factors are located in the HLA-DR,DQ class II region (IDDM1) and at a variable number tandem repeat (VNTR) in the 5 region of the insulin gene (IDDM2). Recent long-term prospective Finnish studies have strongly suggested that infections with enteroviruses such as Coxsackievirus may trigger the autoimmune process (2–5). For example, increased frequencies of serum enterovirus antigens and antibodies toward enterovirus were observed during the preclinical phase in children who subsequently developed diabetes (2,4,5). Finnish researchers also demonstrated a temporal association between appearance of antiviral antibodies and islet cell autoantibodies in prediabetic siblings of type 1 diabetic patients (3,5). Similarly, children who were positive for islet autoantibodies had significantly higher levels of IgG antibodies toward Coxsackie B4 virus than control children (6), and nondiabetic children with islet cell autoantibodies had stronger T-cell reactivity against enterovirus proteins than children without such autoantibodies (7). Virus infections induce interferon, which, through a complex signal transduction pathway, induces the OAS genes encoding the key antiviral enzyme 2 5 -oligoadenylate synthetase (2 5 AS). This enzyme synthesizes oligoadenylates that activate a latent RNase (RNaseL), which then degrades viral and cellular RNA, inhibiting virus replication and promoting the death of infected cells. The innate 2 5 AS-RNaseL antiviral defense system is critical for controlling infection with novel viruses before development of an adaptive (antigen-specific) immune response. We previously showed (8) that basal activity of 2 5 AS was significantly increased in patients with type 1 diabetes compared with healthy control subjects (P 0.001). Furthermore, new analysis of data from our earlier study From the Department of Medical Genetics, University of British Columbia, Vancouver, Canada; the Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; the Steno Diabetes Centre, Gentofte, Denmark; and the Department of Endocrinology, Odense University, Odense, Denmark. Address correspondence and reprint requests to Dr. L. Leigh Field, BC Research Institute for Children’s and Women’s Health, 950 W. 28 Ave., Vancouver, BC, V5Z 4H4, Canada. E-mail: firstname.lastname@example.org or email@example.com. Received for publication 19 October 2004 and accepted in revised form 7 January 2005. L.L.F. and V.B.-N. contributed equally to this study. 2 5 AS, 2 5 -oligoadenylate synthetase; RNaseL, latent RNase; SNP, single nucleotide polymorphism; VNTR, variable number tandem repeat. © 2005 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.