title: Association of common variation in the HNF1alpha gene region with risk of type 2 diabetes.
abstract: It is currently unclear how often genes that are mutated to cause rare, early-onset monogenic forms of disease also harbor common variants that contribute to the more typical polygenic form of each disease. The gene for MODY3 diabetes, HNF1alpha, lies in a region that has shown linkage to late-onset type 2 diabetes (12q24, NIDDM2), and previous association studies have suggested a weak trend toward association for common missense variants in HNF1alpha with glucose-related traits. Based on genotyping of 79 common SNPs in the 118 kb spanning HNF1alpha, we selected 21 haplotype tag single nucleotide polymorphisms (SNPs) and genotyped them in >4,000 diabetic patients and control subjects from Sweden, Finland, and Canada. Several SNPs from the coding region and 5' of the gene demonstrated nominal association with type 2 diabetes, with the most significant marker (rs1920792) having an odds ratio of 1.17 and a P value of 0.002. We then genotyped three SNPs with the strongest evidence for association to type 2 diabetes (rs1920792, I27L, and A98V) in an additional 4,400 type 2 diabetic and control subjects from North America and Poland and compared our results with those of the original sample and of Weedon et al. None of the results were consistently observed across all samples, with the possible exception of a modest association of the rare (3-5%) A98V variant. These results indicate that common variants in HNF1alpha either play no role in type 2 diabetes, a very small role, or a role that cannot be consistently observed without consideration of as yet unmeasured genetic or environmental modifiers.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Wendy
authors.initials: W
authors.lastname: Winckler
authors.forename: Noël P
authors.initials: NP
authors.lastname: Burtt
authors.forename: Johan
authors.initials: J
authors.lastname: Holmkvist
authors.forename: Camilla
authors.initials: C
authors.lastname: Cervin
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: David
authors.initials: D
authors.lastname: Altshuler
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
mesh_terms: D016022:Case-Control Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D051537:Hepatocyte Nuclear Factor 1; D051538:Hepatocyte Nuclear Factor 1-alpha; D006801:Humans; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D009687:Nuclear Proteins; D014157:Transcription Factors; D051537:Hepatocyte Nuclear Factor 1