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

From the Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke’s Hospital, Cambridge, U.K

Address correspondence and reprint requests to John A. Todd, Cambridge Institute for Medical Research (CIMR), Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Wellcome Trust/MRC Building, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 2XY, U.K. E-mail: john.todd{at}cimr.cam.ac.uk

Abbreviations: nsSNP, nonsynonymous SNP; SNP, single nucleotide polymorphism; TDT, transmission/disequilbrium test

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 2'5'-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.

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