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Diabetes 53:3002-3006, 2004
© 2004 by the American Diabetes Association, Inc.

Brief Genetics Report

Common Variants of the Hepatocyte Nuclear Factor-4{alpha} P2 Promoter Are Associated With Type 2 Diabetes in the U.K. Population

Michael N. Weedon1, Katharine R. Owen1, Beverley Shields1, Graham Hitman2, Mark Walker3, Mark I. McCarthy4, Latisha D. Love-Gregory5, M. Alan Permutt5, Andrew T. Hattersley1, and Timothy M. Frayling1

1 Department of Diabetes Research & Vascular Medicine, Peninsula Medical School, Exeter, U.K
2 Department of Diabetes & Metabolic Medicine, Barts and the London, Queen Mary School of Medicine and Dentistry, University of London, London, U.K
3 Department of Medicine, School of Medicine, Newcastle upon-Tyne, U.K
4 Diabetes Research Laboratories, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, U.K
5 Division of Endocrinology, Diabetes and Metabolism, Washington University School of Medicine, St. Louis, Missouri

Hepatocyte nuclear factor (HNF)-4{alpha} is part of a transcription factor network that is key for the development and function of the ß-cell. Rare mutations in the HNF4{alpha} gene cause maturity-onset diabetes of the young. A number of type 2 diabetes linkage studies have found evidence of linkage to 20q12–13.1 where the HNF4{alpha} gene is located. Two recent studies have found an association between four common variants of the alternative P2 promoter region and type 2 diabetes. These variants are in strong linkage disequilibrium, and the minor alleles define one common risk haplotype. In both studies, the risk haplotype explained a large proportion of the evidence of linkage to 20q12–13.1. We aimed to assess this haplotype in a U.K. Caucasian study of 5,256 subjects. We typed two single nucleotide polymorphisms tagging the risk haplotype (rs4810424 and rs2144908) and found evidence of association in both case-control and family-based studies; rs4810424 marginally demonstrated the stronger association with an overall estimated odds ratio of 1.15 (95% CI 1.02–1.33) (P = 0.02). The effect of the P2 haplotype on type 2 diabetes risk is less than in the initial studies, probably reflecting that these studies used 20q12–13.1–linked cases. In conclusion, we have replicated the association of the HNF4{alpha} P2 promoter haplotype with type 2 diabetes in a U.K. Caucasian population where there is no evidence of linkage to 20q.

Address correspondence and reprint requests to Dr. Tim Frayling, Molecular Genetics, Peninsula Medical School, Barrack Road, Exeter, EX2 5DW. E-mail: t.m.frayling{at}exeter.ac.uk


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Copyright © 2004 by the American Diabetes Association.