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- Title
Population-specific risk of type 2 diabetes conferred by HNF4A P2 promoter variants: a lesson for replication studies.
- Authors
Barroso I; Luan J; Wheeler E; Whittaker P; Wasson J; Zeggini E; Weedon MN; Hunt S; Venkatesh R; Frayling TM; Delgado M; Neuman RJ; Zhao J; Sherva R; Glaser B; Walker M; Hitman G; McCarthy MI; Hattersley AT; Permutt MA
- Abstract
<bold>Objective: </bold>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.<bold>Research Design and Methods: </bold>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.<bold>Results: </bold>Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and type 2 diabetes in the Ashkenazim (n = 991; P < 1.6 x 10(-6)). Importantly, these associations are significant in a subset of Ashkenazi samples (n = 531) not previously tested for association with P2 SNPs (odds ratio [OR] approximately 1.7; P < 0.002), thus providing replication within the Ashkenazim. In the U.K. populations, this association was not significant (n = 4,022; P > 0.5), and the estimate for the OR was much smaller (OR 1.04; [95%CI 0.91-1.19]).<bold>Conclusions: </bold>These data indicate that the risk conferred by HNF4A P2 is significantly different between U.K. and Ashkenazi populations (P < 0.00007), suggesting that the underlying causal variant remains unidentified. Interactions with other genetic or environmental factors may also contribute to this difference in risk between populations.
- Publication
Diabetes, 2008, Vol 57, Issue 11, p3161
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/db08-0719