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

  1. L. Leigh Field1,
  2. Vagn Bonnevie-Nielsen2,
  3. Flemming Pociot3,
  4. Shao Lu1,
  5. Thomas B. Nielsen4 and
  6. Henning Beck-Nielsen4
  1. 1Department of Medical Genetics, University of British Columbia, Vancouver, Canada
  2. 2Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada
  3. 3Steno Diabetes Centre, Gentofte, Denmark
  4. 4Department of Endocrinology, Odense University, Odense, Denmark
  1. 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: llfield{at}interchange.ubc.ca or bonnevie{at}interchange.ubc.ca

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 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.

Footnotes

  • L.L.F. and V.B.-N. contributed equally to this study.

    • Accepted January 7, 2005.
    • Received October 19, 2004.
| Table of Contents