Association of Human Endogenous Retrovirus K-18 Polymorphisms With Type 1 Diabetes
- 1Department of Genetics and Microbiology, University of Geneva Medical School, Geneva, Switzerland
- 2Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, U.K
- Address correspondence and reprint requests to B. Conrad or John A. Todd, Department of Genetics & Microbiology, CMU, 1 rue Michel Servet, University of Geneva Medical School, 1211 Geneva 4, Switzerland. E-mail: b.conrad{at}medecine.unige.ch
Abstract
Several lines of evidence suggest the involvement of the human endogenous retrovirus (HERV)-K18 in the etiology of type 1 diabetes. HERV-K18 encodes for a T-cell superantigen (SAg). T-cells with T-cell receptor Vβ7 chains reactive to the SAg and HERV-K18 mRNA were enriched in the tissues at the onset of the disease. HERV-K18 transcription and SAg function in cells capable of efficient presentation are induced by proinflammatory stimuli such as viruses and interferon-α and may trigger progression of disease to insulitis or from insulitis to overt diabetes. Allelic variation of HERV-K18 or the DNA flanking it, the CD48 gene, could modulate genetic susceptibility. Analysis of 14 polymorphisms in the locus using 754 diabetic families provided positive evidence of association of three variants belonging to a single haplotype (P = 0.0026), present at 21.8% frequency in the population. Genotype analysis suggested a dominantly protective effect of this haplotype (P = 0.0061). Further genetic and functional analyses are required to confirm these findings.
Footnotes
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S.M. and W.Y.S.W. contributed equally to this work
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B.C. holds stock in NovImmune, a company that develops diabetes drugs.
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- Accepted November 17, 2003.
- Received October 13, 2003.
- DIABETES
