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Population-Specific Risk of Type 2 Diabetes Conferred by HAT4A P2 Promoter Variants: A Lesson for Replication Studies

Lookup NU author(s): Professor Mark Walker


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OBJECTIVE-Single nucleotide polymorphisms (SNPs) in the P2 promoter region of HNF4A were originally shown to be associated with predisposition for type 2 diabetes in Finnish, Ashkenazi, and, more recently, Scandinavian populations, but they generated conflicting results in additional populations. We aimed to investigate whether data from a large-scale mapping approach would replicate this association in novel Ashkenazi samples and in U.K. populations and whether these data would allow us to refine the association signal. RESEARCH DESIGN AND METHODS-Using a dense linkage disequilibrium map of 20q we selected SNPs from a 10-Mb interval centered on HNF4A. In a staged approach, we first typed 4,608 SNPs in case-control populations from four U.K. populations and an Ashkenazi population (n = 2,516). In phase 2, a subset of 763 SNPs was genotyped in 2,513 additional samples from the same populations. RESULTS-Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and type 2 diabetes in the Ashkenazim (n = 991; P 0.5), and the estimate for the OR was much smaller (OR 1.04; [95%CI 0.91-1.19]). CONCLUSIONS-These data indicate that the risk conferred by HNF4A P2 is significantly different between U.K. and Ashkenazi populations (P

Publication metadata

Author(s): Barroso I, Luan JA, Wheeler E, Whittaker P, Wasson J, Zeggini E, Weedon MN, Hunt S, Venkatesh R, Frayling TM, Delgado M, Neuman RJ, Zhao JH, Sherva R, Glaser B, Walker M, Hitman G, McCarthy MI, Hattersley AT, Permutt MA, Wareham NJ, Deloukas P

Publication type: Article

Publication status: Published

Journal: Diabetes

Year: 2008

Volume: 57

Issue: 11

Pages: 3161-3165

ISSN (print): 0012-1797

ISSN (electronic): 1939-327X

Publisher: American Diabetes Association


DOI: 10.2337/db08-0719


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Funder referenceFunder name
Medical Research Center
Novo Nordisk, Denmark
Diabetes Care in Israel
Diabetes UK
Russell Berrie Foundation
Wellcome Trust
5040Chief Scientist Office of the Israel Ministry of Health
LSHM-CT-2003-503041European Union FP6
R01 DK049583National Institutes of Health