Population-Specific Risk of Type 2 Diabetes Conferred by HNF4A P2 Promoter Variants

A Lesson for Replication Studies

  1. Inês Barroso1,
  2. Jian’an Luan2,
  3. Eleanor Wheeler1,
  4. Pamela Whittaker1,
  5. Jon Wasson3,
  6. Eleftheria Zeggini45,
  7. Michael N. Weedon6,
  8. Sarah Hunt1,
  9. Ranganath Venkatesh1,
  10. Timothy M. Frayling6,
  11. Marcos Delgado14,
  12. Rosalind J. Neuman3,
  13. Jinghua Zhao2,
  14. Richard Sherva3,
  15. Benjamin Glaser47,
  16. Mark Walker8,
  17. Graham Hitman9,
  18. Mark I. McCarthy45,
  19. Andrew T. Hattersley6,
  20. M. Alan Permutt3,
  21. Nicholas J. Wareham2 and
  22. Panagiotis Deloukas1
  1. 1Wellcome Trust Sanger Institute, Hinxton, Cambridge, U.K
  2. 2Medical Research Council Epidemiology Unit, Institute of Metabolic Science, Cambridge, U.K
  3. 3Washington University School of Medicine, St. Louis, Missouri
  4. 4Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, U.K
  5. 5Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K
  6. 6Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, U.K
  7. 7Endocrine and Metabolism Service, Hadassah Hebrew University Medical Center, Jerusalem, Israel
  8. 8Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, Newcastle, U.K
  9. 9Centre for Diabetes and Metabolic Medicine, Barts, and the Queen Mary School of Medicine and Dentistry, University of London, London, U.K
  1. Corresponding author: Inês Barroso, ib1{at}


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 < 1.6 × 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] ∼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.


  • Published ahead of print at on 26 August 2008.

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    • Accepted August 15, 2008.
    • Received April 12, 2008.
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  1. Diabetes vol. 57 no. 11 3161-3165
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