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Association Testing of Variants in the Hepatocyte Nuclear Factor 4 Gene With Risk of Type 2 Diabetes in 7,883 People

¹ Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
² Department of Genetics, Harvard Medical School, Boston, Massachusetts
³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
⁴ Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
⁵ Department of Medicine, Helsinki University Central Hospital, Folkhalsan Genetic Institute, Folkhalsan Research Center, and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
⁶ University of Montreal Community Genomic Center, Chicoutimi Hospital, Montreal, Quebec, Canada
⁷ McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada
⁸ Genomics Collaborative, Inc., Cambridge, Massachusetts
⁹ Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
¹⁰ Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts
¹¹ Department of Medicine, Harvard Medical School, Boston, Massachusetts

Two recent publications reported association of common polymorphisms in the P2 promoter of hepatocyte nuclear factor 4 (HNF4) (the MODY1 gene) with risk for type 2 diabetes. We attempted to reproduce this putative association by genotyping 11 single nucleotide polymorphism (SNPs) spanning the HNF4 coding region and the P2 promoter in >3,400 patients and control subjects from Sweden, Finland, and Canada. One SNP that was consistently associated in the two previous reports (rs1884613, in the P2 promoter region) also trended in the same direction in our sample, albeit with a lower estimated odds ratio (OR) of 1.11 (P = 0.05, one-tailed). We genotyped this SNP (rs1884613) in an additional 4,400 subjects from North America and Poland. In this sample, the association was not confirmed and trended in the opposite direction (OR 0.88). Meta-analysis of our combined sample of 7,883 people (three times larger than the two initial reports combined) yielded an OR of 0.97 (P = 0.27). Finally, we provide an updated analysis of haplotype structure in the region to guide any further investigation of common variation in HNF4. Although our combined results fail to replicate the previously reported association of common variants in HNF4 with risk for type 2 diabetes, we cannot exclude an effect smaller than that originally proposed, heterogeneity among samples, variation in as-yet-unmeasured genotypic or environmental modifiers, or true association secondary to linkage disequilibrium (LD) with as-yet-undiscovered variant(s) in the region.

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