title: A role for coding functional variants in HNF4A in type 2 diabetes susceptibility.
abstract: OBJECTIVE
  Rare mutations in the gene HNF4A, encoding the transcription factor hepatocyte nuclear factor 4α (HNF-4A), account for ~5% of cases of MODY and more frequent variants in this gene may be involved in multifactorial forms of diabetes. Two low-frequency, non-synonymous variants in HNF4A (V255M, minor allele frequency [MAF] ~0.1%; T130I, MAF ~3.0%)-known to influence downstream HNF-4A target gene expression-are of interest, but previous type 2 diabetes association reports were inconclusive. We aimed to evaluate the contribution of these variants to type 2 diabetes susceptibility through large-scale association analysis.
  
  
  METHODS
  We genotyped both variants in at least 5,745 cases and 14,756 population controls from the UK and Denmark. We also undertook an expanded association analysis that included previously reported and novel genotype data obtained in Danish, Finnish, Canadian and Swedish samples. A meta-analysis incorporating all published association studies of the T130I variant was subsequently carried out in a maximum sample size of 14,279 cases and 26,835 controls.
  
  
  RESULTS
  We found no association between V255M and type 2 diabetes in either the initial (p = 0.28) or the expanded analysis (p = 0.44). However, T130I demonstrated a modest association with type 2 diabetes in the UK and Danish samples (additive per allele OR 1.17 [95% CI 1.08-1.28]; p = 1.5 × 10⁻⁴), which was strengthened in the meta-analysis (OR 1.20 [95% CI 1.10-1.30]; p = 2.1 × 10⁻⁵).
  
  
  CONCLUSIONS
  Our data are consistent with T130I as a low-frequency variant influencing type 2 diabetes risk, but are not conclusive when judged against stringent standards for genome-wide significance. This study exemplifies the difficulties encountered in association testing of low-frequency variants.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Churchill Hospital, Headington, UK.
authors.forename: B
authors.initials: B
authors.lastname: Jafar-Mohammadi
authors.forename: C J
authors.initials: CJ
authors.lastname: Groves
authors.forename: A P
authors.initials: AP
authors.lastname: Gjesing
authors.forename: B M
authors.initials: BM
authors.lastname: Herrera
authors.forename: W
authors.initials: W
authors.lastname: Winckler
authors.forename: H M
authors.initials: HM
authors.lastname: Stringham
authors.forename: A P
authors.initials: AP
authors.lastname: Morris
authors.forename: T
authors.initials: T
authors.lastname: Lauritzen
authors.forename: A S F
authors.initials: AS
authors.lastname: Doney
authors.forename: A D
authors.initials: AD
authors.lastname: Morris
authors.forename: M N
authors.initials: MN
authors.lastname: Weedon
authors.forename: A J
authors.initials: AJ
authors.lastname: Swift
authors.forename: J
authors.initials: J
authors.lastname: Kuusisto
authors.forename: M
authors.initials: M
authors.lastname: Laakso
authors.forename: D
authors.initials: D
authors.lastname: Altshuler
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: F S
authors.initials: FS
authors.lastname: Collins
authors.forename: M
authors.initials: M
authors.lastname: Boehnke
authors.forename: T
authors.initials: T
authors.lastname: Hansen
authors.forename: O
authors.initials: O
authors.lastname: Pedersen
authors.forename: C N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: T M
authors.initials: TM
authors.lastname: Frayling
authors.forename: A L
authors.initials: AL
authors.lastname: Gloyn
authors.forename: M I
authors.initials: MI
authors.lastname: McCarthy
mesh_terms: D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation
chemical_list: C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4