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Hepatocyte Nuclear Factor-4 P2 Promoter Haplotypes Are Associated With Type 2 Diabetes in the Japanese Population

¹ Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
² Department of Clinical Bioinformatics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
³ CREST, Japan Science and Technology Corporation (JST), Tokyo, Japan
⁴ National Institute of Health and Nutrition, Tokyo, Japan
⁵ Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo, Japan
⁶ Hiroshima Atomic Bomb Casualty Council Health Management Center, Hiroshima, Japan
⁷ Department of Endocrinology and Metabolism, International Medical Center of Japan, Tokyo, Japan
⁸ Department of Human Genetics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
⁹ CNRS 8090, Institut de Biologie de Lille, Institute Pasteur and CHU Lille, Lille, France
¹⁰ Department of Cardiovascular Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Address correspondence and reprint requests to Dr. Takashi Kadowaki, Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp

Abbreviations: HNF, hepatocyte nuclear factor; LD, linkage disequilibrium; MODY, maturity-onset diabetes of the young; SNP, single nucleotide polymorphism

Hepatocyte nuclear factor (HNF)-4 is a transcription factor known as a key molecule in the development and functions of the ß-cells. In a previously performed genome-wide scan of Japanese type 2 diabetic sibpairs, we observed linkage of type 2 diabetes to chromosome 20q12-q13, a region in which the HNF4A gene is located. Recent studies have reported associations between type 2 diabetes and polymorphisms in the P2 promoter region specific to ß-cells. In this study, we attempted to assess whether the HNF4A gene plays a role in the genetic susceptibility to type 2 diabetes in the Japanese population by analyzing polymorphisms and haplotypes of the HNF4A gene. Linkage disequilibrium across the P2 promoter region was preserved in the Japanese population, consistent with previous reports. Although none of the individual polymorphisms examined showed any significant association with type 2 diabetes, we found very strong evidence of the association between type 2 diabetes and the haplotype consisting of two polymorphisms in the P2 promoter region of the HNF4A gene (P = 3.82 x 10^–4). In contrast, there was no association between type 2 diabetes and haplotypes consisting of polymorphisms not located in the P2 promoter region, suggesting that the type 2 diabetes susceptibility loci are localized in the P2 promoter region of the HNF4A gene. The association was replicated using two additional cohorts (P = 1.51 x 10^–4 and 0.019, respectively). The results of the present analysis revealed that the HNF4A gene might be a type 2 diabetes susceptibility gene common to different ethnic groups. The study also suggested the possible existence of an as-yet-unidentified but functional polymorphism in the P2 promoter region of the HNF4A gene that directly influences susceptibility to type 2 diabetes.

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