OAS1 Splice Site Polymorphism Controlling Antiviral Enzyme Activity Influences Susceptibility to Type 1 Diabetes

Abstract

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 25-oligoadenylate synthetase (25AS) 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 25AS is strongly associated with basal 25AS 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 T ype 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 5Ј 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 ...

Molecular Genetic Analysis of the Idd4 Locus Implicates the IFN Response in Type 1 Diabetes Susceptibility in Nonobese Diabetic Mice

“…OAS proteins produce 2Ј-5Ј-oligoadenylates, required to activate latent ribonucleases, leading to viral RNA degradation and inhibition of viral replication. Recent evidence suggested that an OAS1 splice site polymorphism that affects enzyme activity (55) is associated with susceptibility to T1D (56), providing a functional link between antiviral/IFN response and autoimmunity.…”

Systematic evaluation of the effect of common SNPs on pre-mRNA splicing

“…Host susceptibility to viral infection in type I diabetes has been shown to be associated with variation in the OAS1 gene (oligoadenylate synthetase 1), for which a splice SNP, rs10774671, was identified (Field et al, 2005). The remaining 15 splice SNPs have not been reported to be associated with a specific phenotype, but the information provided here may contribute to a better understanding of the functional relevance of the respective loci, particularly since an increasing number of disease-associated loci are being identified in hypothesis-free genome-wide association studies .…”

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

“…interdependence between sibling genotypes was ignored and the P value is not very small, this difference between diabetic and healthy siblings may be a false-positive. A more important caveat regarding the interpretation of their data arises from their results using the AFBAC (affected-family based controls) method (10) to compare the frequencies of transmitted and untransmitted alleles from parents to 368 diabetic siblings (one per family) and to 198 unaffected siblings; they found no evidence of an association between type 1 diabetes and the A/G splice-site SNP in the affected siblings (P ϭ 0.27) but did find evidence of an increased frequency of the A allele in unaffected siblings (A allele frequency 0.71 in transmitted vs. 0.61 in nontransmitted alleles; P ϭ 0.003) (9). Consequently, Field et al concluded that the A allele was having a protective effect in the unaffected siblings.…”

“…Field et al (9) recently reported that the A allele of an A/G splice-site single nucleotide polymorphism (SNP) (rs10774671) in the OAS1 gene, encoding 2Ј5Ј-oligoadenylate synthetase, had a type 1 diabetes protective effect in 401 unaffected siblings but no effect in 835 affected siblings. interdependence between sibling genotypes was ignored and the P value is not very small, this difference between diabetic and healthy siblings may be a false-positive.…”