title: Effect of common polymorphisms in the HNF4alpha promoter on susceptibility to type 2 diabetes in the French Caucasian population.
abstract: OBJECTIVE
  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
  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.affiliation: CNRS 8090-Institut de Biologie, Institut Pasteur de Lille, 1 rue du Professeur Calmette, BP 245, 59019, Lille, France. martine.vaxillaire@pasteur-lille.fr
authors.forename: M
authors.initials: M
authors.lastname: Vaxillaire
authors.forename: C
authors.initials: C
authors.lastname: Dina
authors.forename: S
authors.initials: S
authors.lastname: Lobbens
authors.forename: A
authors.initials: A
authors.lastname: Dechaume
authors.forename: V
authors.initials: V
authors.lastname: Vasseur-Delannoy
authors.forename: N
authors.initials: N
authors.lastname: Helbecque
authors.forename: G
authors.initials: G
authors.lastname: Charpentier
authors.forename: P
authors.initials: P
authors.lastname: Froguel
mesh_terms: D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D005387:Finland; D005602:France; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D010750:Phosphoproteins / Q000235:genetics*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics*; D044465:White People
chemical_list: D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D014157:Transcription Factors
references.citation: J Clin Invest. 2003 Dec;112(11):1762-72
references.pmid: 14660752
references.citation: J Clin Invest. 1998 Feb 1;101(3):521-6
references.pmid: 9449683
references.citation: N Engl J Med. 1993 May 27;328(21):1568; author reply 1569
references.pmid: 8479502
references.citation: Proc Natl Acad Sci U S A. 2001 Dec 4;98(25):14481-6
references.pmid: 11717395
references.citation: Hum Mol Genet. 2001 Sep 15;10(19):2089-97
references.pmid: 11590126
references.citation: Diabetologia. 2002 Sep;45(9):1344-8
references.pmid: 12242469
references.citation: Am J Hum Genet. 2000 Dec;67(6):1470-80
references.pmid: 11067779
references.citation: Diabetes. 1998 Jun;47(6):970-2
references.pmid: 9604877
references.citation: Diabetes. 2002 Dec;51 Suppl 3:S308-15
references.pmid: 12475768
references.citation: IARC Sci Publ. 1980;(32):5-338
references.pmid: 7216345
references.citation: Diabetes. 2004 Apr;53(4):1134-40
references.pmid: 15047632
references.citation: Hum Mol Genet. 1997 Sep;6(9):1401-8
references.pmid: 9285775
references.citation: Nature. 1996 Dec 5;384(6608):458-60
references.pmid: 8945471
references.citation: J Natl Cancer Inst. 1959 Apr;22(4):719-48
references.pmid: 13655060
references.citation: Diabetes. 2004 Apr;53(4):1141-9
references.pmid: 15047633
references.citation: Proc Natl Acad Sci U S A. 1999 Mar 2;96(5):2198-203
references.pmid: 10051618