AIMS/HYPOTHESIS: The gene encoding HNF-4alpha, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4alpha P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population. METHODS: Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a case-control study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4alpha region had been shown. RESULTS: The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4alpha was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage. CONCLUSIONS/ INTERPRETATION: None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4alpha and type 2 diabetes in several ethnic groups.
AIMS/HYPOTHESIS: The gene encoding HNF-4alpha, an orphan nuclear receptor playing critical roles in embryogenesis and metabolism by regulating gene expression in pancreatic beta cells, liver, and other tissues, is localised to chromosome 20q13, where linkage to type 2 diabetes has been shown in multiple studies. As two reports have independently demonstrated a convincing association with variants adjacent to the HNF-4alpha P2 promoter in Finnish and Ashkenazi Jewish populations, we evaluated their contribution to diabetes risk in the French Caucasian population. METHODS: Genotypes for four haplotype tag SNPs were analysed for association with diabetes in a case-control study of 744 unrelated type 2 diabetic patients and 686 normoglycaemic subjects, and for linkage in 148 diabetic families in whom significant linkage to the HNF4alpha region had been shown. RESULTS: The association seen in the Finnish and Ashkenazi studies for SNPs rs2144908 and rs1884614 located within a haplotype block encompassing the beta cell promoter P2 of HNF-4alpha was not replicated in our study; in French Caucasians the minor allele prevalence was increased in control subjects [odds ratio (OR) 0.80, uncorrected p=0.022 for rs2144908; OR 0.82 uncorrected p=0.058 for rs1884614]. Furthermore, none of the SNPs tested in the French familial sample was associated with diabetes, nor do they appear to contribute to the linkage. CONCLUSIONS/ INTERPRETATION: None of the previously associated SNPs confer an increased risk for diabetes in French Caucasians. A large meta-analysis of association studies will determine whether there is a consistent association between particular SNPs upstream of HNF-4alpha and type 2 diabetes in several ethnic groups.
Authors: Marshall Alan Permutt; Jonathan Wasson; Latisha Love-Gregory; Jiyan Ma; Gary Skolnick; Brian Suarez; Jennifer Lin; Benjamin Glaser Journal: Diabetes Date: 2002-12 Impact factor: 9.461
Authors: H Thomas; K Jaschkowitz; M Bulman; T M Frayling; S M Mitchell; S Roosen; A Lingott-Frieg; C J Tack; S Ellard; G U Ryffel; A T Hattersley Journal: Hum Mol Genet Date: 2001-09-15 Impact factor: 6.150
Authors: E H Hani; L Suaud; P Boutin; J C Chèvre; E Durand; A Philippi; F Demenais; N Vionnet; H Furuta; G Velho; G I Bell; B Laine; P Froguel Journal: J Clin Invest Date: 1998-02-01 Impact factor: 14.808
Authors: N Vionnet; El H Hani; S Dupont; S Gallina; S Francke; S Dotte; F De Matos; E Durand; F Leprêtre; C Lecoeur; P Gallina; L Zekiri; C Dina; P Froguel Journal: Am J Hum Genet Date: 2000-11-06 Impact factor: 11.025
Authors: Elina Suviolahti; Laura J Oksanen; Miina Ohman; Rita M Cantor; Martin Ridderstrale; Tiinamaija Tuomi; Jaakko Kaprio; Aila Rissanen; Pertti Mustajoki; Pekka Jousilahti; Erkki Vartiainen; Kaisa Silander; Riika Kilpikari; Veikko Salomaa; Leif Groop; Kimmo Kontula; Leena Peltonen; Päivi Pajukanta Journal: J Clin Invest Date: 2003-12 Impact factor: 14.808
Authors: S M S Mitchell; M Vaxillaire; H Thomas; M Parrizas; Y Benmezroua; A Costa; T Hansen; K R Owen; T Tuomi; F Pirie; G U Ryffel; J Ferrer; P Froguel; A T Hattersley; T M Frayling Journal: Diabetologia Date: 2002-07-19 Impact factor: 10.122
Authors: Valérie Marcil; Devendra Amre; Ernest G Seidman; François Boudreau; Fernand P Gendron; Daniel Ménard; Jean François Beaulieu; Daniel Sinnett; Marie Lambert; Emile Levy Journal: PLoS One Date: 2015-02-11 Impact factor: 3.240
Authors: Inês Barroso; Jian'an Luan; Eleanor Wheeler; Pamela Whittaker; Jon Wasson; Eleftheria Zeggini; Michael N Weedon; Sarah Hunt; Ranganath Venkatesh; Timothy M Frayling; Marcos Delgado; Rosalind J Neuman; Jinghua Zhao; Richard Sherva; Benjamin Glaser; Mark Walker; Graham Hitman; Mark I McCarthy; Andrew T Hattersley; M Alan Permutt; Nicholas J Wareham; Panagiotis Deloukas Journal: Diabetes Date: 2008-08-26 Impact factor: 9.461
Authors: V Marcil; D Sinnett; E Seidman; F Boudreau; F-P Gendron; J-F Beaulieu; D Menard; M Lambert; A Bitton; R Sanchez; D Amre; E Levy Journal: Genes Immun Date: 2012-08-23 Impact factor: 2.676