title: Association testing of variants in the hepatocyte nuclear factor 4alpha gene with risk of type 2 diabetes in 7,883 people.
abstract: Two recent publications reported association of common polymorphisms in the P2 promoter of hepatocyte nuclear factor 4alpha (HNF4alpha) (the MODY1 gene) with risk for type 2 diabetes. We attempted to reproduce this putative association by genotyping 11 single nucleotide polymorphism (SNPs) spanning the HNF4alpha coding region and the P2 promoter in >3,400 patients and control subjects from Sweden, Finland, and Canada. One SNP that was consistently associated in the two previous reports (rs1884613, in the P2 promoter region) also trended in the same direction in our sample, albeit with a lower estimated odds ratio (OR) of 1.11 (P = 0.05, one-tailed). We genotyped this SNP (rs1884613) in an additional 4,400 subjects from North America and Poland. In this sample, the association was not confirmed and trended in the opposite direction (OR 0.88). Meta-analysis of our combined sample of 7,883 people (three times larger than the two initial reports combined) yielded an OR of 0.97 (P = 0.27). Finally, we provide an updated analysis of haplotype structure in the region to guide any further investigation of common variation in HNF4alpha. Although our combined results fail to replicate the previously reported association of common variants in HNF4alpha with risk for type 2 diabetes, we cannot exclude an effect smaller than that originally proposed, heterogeneity among samples, variation in as-yet-unmeasured genotypic or environmental modifiers, or true association secondary to linkage disequilibrium (LD) with as-yet-undiscovered variant(s) in the region.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Winckler
authors.forename: Robert R
authors.initials: RR
authors.lastname: Graham
authors.forename: Paul I W
authors.initials: PI
authors.lastname: de Bakker
authors.forename: Maria
authors.initials: M
authors.lastname: Sun
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.forename: Tiinamaija
authors.initials: T
authors.lastname: Tuomi
authors.forename: Daniel
authors.initials: D
authors.lastname: Gaudet
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Ardlie
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Joel N
authors.initials: JN
authors.lastname: Hirschhorn
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
authors.forename: David
authors.initials: D
authors.lastname: Altshuler
mesh_terms: D000328:Adult; D002874:Chromosome Mapping; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D051557:Hepatocyte Nuclear Factor 4; D006801:Humans; D008875:Middle Aged; D016017:Odds Ratio; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012307:Risk Factors; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D010750:Phosphoproteins; D014157:Transcription Factors