title: Hepatocyte nuclear factor-4alpha P2 promoter haplotypes are associated with type 2 diabetes in the Japanese population.
abstract: Hepatocyte nuclear factor (HNF)-4alpha is a transcription factor known as a key molecule in the development and functions of the beta-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 beta-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.
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hara
authors.forename: Momoko
authors.initials: M
authors.lastname: Horikoshi
authors.forename: Hiroji
authors.initials: H
authors.lastname: Kitazato
authors.forename: Chikako
authors.initials: C
authors.lastname: Ito
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Noda
authors.forename: Jun
authors.initials: J
authors.lastname: Ohashi
authors.forename: Philippe
authors.initials: P
authors.lastname: Froguel
authors.forename: Katsushi
authors.initials: K
authors.lastname: Tokunaga
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Ryozo
authors.initials: R
authors.lastname: Nagai
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
mesh_terms: D002874:Chromosome Mapping; D002890:Chromosomes, Human, Pair 20; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D007564:Japan; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012016:Reference Values
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4