title: Population-specific risk of type 2 diabetes conferred by HNF4A P2 promoter variants: a lesson for replication studies.
abstract: 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.
  
  
  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 < 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]).
  
  
  CONCLUSIONS
  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.
authors: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK. ib1@sanger.ac.uk
authors: Inês
authors: I
authors: Barroso
authors: Jian'an
authors: J
authors: Luan
authors: Eleanor
authors: E
authors: Wheeler
authors: Pamela
authors: P
authors: Whittaker
authors: Jon
authors: J
authors: Wasson
authors: Eleftheria
authors: E
authors: Zeggini
authors: Michael N
authors: MN
authors: Weedon
authors: Sarah
authors: S
authors: Hunt
authors: Ranganath
authors: R
authors: Venkatesh
authors: Timothy M
authors: TM
authors: Frayling
authors: Marcos
authors: M
authors: Delgado
authors: Rosalind J
authors: RJ
authors: Neuman
authors: Jinghua
authors: J
authors: Zhao
authors: Richard
authors: R
authors: Sherva
authors: Benjamin
authors: B
authors: Glaser
authors: Mark
authors: M
authors: Walker
authors: Graham
authors: G
authors: Hitman
authors: Mark I
authors: MI
authors: McCarthy
authors: Andrew T
authors: AT
authors: Hattersley
authors: M Alan
authors: MA
authors: Permutt
authors: Nicholas J
authors: NJ
authors: Wareham
authors: Panagiotis
authors: P
authors: Deloukas
mesh_terms: D003924:Diabetes Mellitus, Type 2 / Q000208:ethnology / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D007585:Jews / Q000235:genetics; D015810:Linkage Disequilibrium; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012307:Risk Factors; D006113:United Kingdom; D044465:White People / Q000235:genetics
chemical_list: D051557:Hepatocyte Nuclear Factor 4