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Population-specific risk of type 2 diabetes (T2D) conferred by HNF4A P2 promoter variants: a lesson for replication studies

¹Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK
²MRC Epidemiology Unit, Institute of Metabolic Science, Cambridge, UK
³Washington University School of Medicine, St. Louis, MO, USA
⁴Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK
⁵Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
⁶Institute of Biomedical and Clinical Science, Peninsula Medical School, Exeter, UK
⁷Endocrine and Metabolism Service, The Hadassah Hebrew University Medical Center, Israel
⁸Diabetes Research Group, School of Clinical Medical Sciences, Newcastle University, UK
⁹Centre for Diabetes and Metabolic Medicine, Barts and the London, Queen Mary School of Medicine and Dentistry, University of London, London, UK

Objective: SNPs in the P2 promoter region of HNF4A associated with T2D predisposition originally in Finnish and Ashkenazim and more recently in Scandinavian populations, but 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 UK populations, and whether these data would allow us to refine the association signal.

Research Design and Methods: Using a dense linkage disequilibrium (LD) map of 20q we selected SNPs from a 10Mb interval centred on HNF4A. In a staged approach we first typed 4608 SNPs in case-control populations from four UK and an Ashkenazi population (N=2516). In phase 2, a subset of 763 SNPs were genotyped in 2513 additional samples from the same populations.

Results: Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and T2D in the Ashkenazim (N=991, p<1.6x10^-6). Importantly these associations are significant in a subset of Ashkenazi samples (N=531) not previously tested for association with P2 SNPs (OR1.7, p<0.002), thus providing replication within the Ashkenazim. In the UK populations this association was not significant (N=4022, p>0.5) and the estimate for the odds ratio 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 UK 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.

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