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Association of Common Variation in the HNF1 Gene Region With Risk of Type 2 Diabetes

¹ Department of Molecular Biology, Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts
² Department of Genetics, Harvard Medical School, Boston, Massachusetts
³ Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, 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

It is currently unclear how often genes that are mutated to cause rare, early-onset monogenic forms of disease also harbor common variants that contribute to the more typical polygenic form of each disease. The gene for MODY3 diabetes, HNF1, lies in a region that has shown linkage to late-onset type 2 diabetes (12q24, NIDDM2), and previous association studies have suggested a weak trend toward association for common missense variants in HNF1 with glucose-related traits. Based on genotyping of 79 common SNPs in the 118 kb spanning HNF1, we selected 21 haplotype tag single nucleotide polymorphisms (SNPs) and genotyped them in >4,000 diabetic patients and control subjects from Sweden, Finland, and Canada. Several SNPs from the coding region and 5' of the gene demonstrated nominal association with type 2 diabetes, with the most significant marker (rs1920792) having an odds ratio of 1.17 and a P value of 0.002. We then genotyped three SNPs with the strongest evidence for association to type 2 diabetes (rs1920792, I27L, and A98V) in an additional 4,400 type 2 diabetic and control subjects from North America and Poland and compared our results with those of the original sample and of Weedon et al. None of the results were consistently observed across all samples, with the possible exception of a modest association of the rare (3–5%) A98V variant. These results indicate that common variants in HNF1 either play no role in type 2 diabetes, a very small role, or a role that cannot be consistently observed without consideration of as yet unmeasured genetic or environmental modifiers.

Abbreviations: CEPH, Centre d’Etude du Polymorphisme Humain; GCI, Genomics Collaborative, Inc; LD, linkage disequilibrium; MODY, maturity-onset diabetes of the young; SNP, single nucleotide polymorphism

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