title: Common variants of the hepatocyte nuclear factor-4alpha P2 promoter are associated with type 2 diabetes in the U.K. population.
abstract: Hepatocyte nuclear factor (HNF)-4alpha is part of a transcription factor network that is key for the development and function of the beta-cell. Rare mutations in the HNF4alpha gene cause maturity-onset diabetes of the young. A number of type 2 diabetes linkage studies have found evidence of linkage to 20q12-13.1 where the HNF4alpha gene is located. Two recent studies have found an association between four common variants of the alternative P2 promoter region and type 2 diabetes. These variants are in strong linkage disequilibrium, and the minor alleles define one common risk haplotype. In both studies, the risk haplotype explained a large proportion of the evidence of linkage to 20q12-13.1. We aimed to assess this haplotype in a U.K. Caucasian study of 5,256 subjects. We typed two single nucleotide polymorphisms tagging the risk haplotype (rs4810424 and rs2144908) and found evidence of association in both case-control and family-based studies; rs4810424 marginally demonstrated the stronger association with an overall estimated odds ratio of 1.15 (95% CI 1.02-1.33) (P = 0.02). The effect of the P2 haplotype on type 2 diabetes risk is less than in the initial studies, probably reflecting that these studies used 20q12-13.1-linked cases. In conclusion, we have replicated the association of the HNF4alpha P2 promoter haplotype with type 2 diabetes in a U.K. Caucasian population where there is no evidence of linkage to 20q.
authors.affiliation: Department of Diabetes Research & Vascular Medicine, Peninsula Medical School, Barrack Road, Exeter, UK.
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Owen
authors.forename: Beverley
authors.initials: B
authors.lastname: Shields
authors.forename: Graham
authors.initials: G
authors.lastname: Hitman
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: Latisha D
authors.initials: LD
authors.lastname: Love-Gregory
authors.forename: M Alan
authors.initials: MA
authors.lastname: Permutt
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
mesh_terms: D000328:Adult; D017668:Age of Onset; D002890:Chromosomes, Human, Pair 20 / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D014644:Genetic Variation; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D012016:Reference Values; D014157:Transcription Factors / Q000235:genetics*; D006113:United Kingdom
chemical_list: D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D014157:Transcription Factors