Association Studies of Genetic Variation in the WFS1 Gene and Type 2 Diabetes in U.K. Populations
- Jayne A.L. Minton1,
- Andrew T. Hattersley2,
- Katharine Owen2,
- Mark I. McCarthy3,
- Mark Walker4,
- Farida Latif1,
- Timothy Barrett1 and
- Timothy M. Frayling2
- 1Section of Medical and Molecular Genetics, Department of Pediatrics and Child Health, The Medical School, University of Birmingham, Edgbaston, U.K.
- 2Department of Diabetes and Vascular Medicine, School of Postgraduate Medicine and Health Sciences, University of Exeter, Exeter, U.K.
- 3Imperial College Genetics and Genomics Research Institute and Division of Medicine, Imperial College, London, U.K.
- 4Department of Medicine, Medical School, University of Newcastle, Newcastle, U.K.
Abstract
Mutations in the WFS1 gene cause β-cell death, resulting in a monogenic form of diabetes known as Wolfram syndrome. The role of variation in WFS1 in type 2 diabetes susceptibility is not known. We sequenced the WFS1 gene in 29 type 2 diabetic probands and identified 12 coding variants. We used 152 parent-offspring trios to look for familial association; the R allele at residue 456 (P = 0.04) and the H allele at residue 611 (P = 0.05) as well as the R456-H611 haplotype (P = 0.032) were overtransmitted to affected offspring from heterozygous parents. In a further cohort of 327 type 2 diabetic subjects and 357 normoglycemic control subjects, the H611 allele and the R456-H611 haplotype were present in more type 2 diabetic subjects than control subjects (one-tailed P = 0.06 and P = 0.023, respectively). In a combined analysis, the H611 allele was present in 60% of all diabetes chromosomes and 55% of all control chromosomes (odds ratio [OR] 1.24 [95% CI 1.03–1.48], P = 0.02), and the R456-H611 haplotype was significantly more frequent in type 2 diabetic subjects than in control subjects (60 vs. 54%, OR 1.29 [95% CI 1.08–1.54], P = 0.0053). Our results provide the first evidence that variation in the WFS1 gene may influence susceptibility to type 2 diabetes.
Footnotes
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Address correspondence and reprint requests to Tim Barrett, Section of Medical and Molecular Genetics, Department of Pediatrics and Child Health, The Medical School, University of Birmingham, Edgbaston, Birmingham, B15 2TT U.K. E-mail: t.g.barrett{at}bham.ac.uk.
Received for publication 20 September 2001 and accepted in revised form 4 January 2002.
EH, Estimated Haplotype; LD, linkage disequilibrium; OR, odds ratio; TDT, transmission disequilibrium test.
- DIABETES
