title: Association studies of insulin receptor substrate 1 gene (IRS1) variants in type 2 diabetes samples enriched for family history and early age of onset.
abstract: The gene encoding insulin receptor substrate-1 (IRS1) represents a strong biological candidate for a contributory role in type 2 diabetes susceptibility. Indeed, functional studies have implicated the G971R variant, and a recent meta-analysis of 27 association studies suggested that carriage of 971R was associated with a 25% increase in disease risk. However, this association has not been evaluated in large samples. The present study genotyped the P512A and G971R IRS1 variants in 971 U.K. type 2 diabetic subjects ascertained for strong family history and/or early onset, as well as 1,257 control subjects matched by ethnicity. There was no evidence for association with type 2 diabetes for either variant. (For example, the odds ratio [OR] for carriage of 971R was 1.11 [95% CI 0.86-1.44, P = 0.44]) An updated meta-analysis (31 studies: 5,104 case and 7,418 control subjects) remained significant for the G971R association (P = 0.025), albeit with a diminished OR (1.15 [95% CI 1.02-1.31]). Additional studies of IRS1 variation will be required to obtain a robust estimate of the overall contribution of IRS1 variation to type 2 diabetes susceptibility, but the current study suggests that previous studies have overestimated the magnitude of this effect.
authors.affiliation: Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Zeggini
authors.forename: James
authors.initials: J
authors.lastname: Parkinson
authors.forename: Stephanie
authors.initials: S
authors.lastname: Halford
authors.forename: Katharine R
authors.initials: KR
authors.lastname: Owen
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
authors.forename: Mark
authors.initials: M
authors.lastname: Walker
authors.forename: Graham A
authors.initials: GA
authors.lastname: Hitman
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Levy
authors.forename: Mike J
authors.initials: MJ
authors.lastname: Sampson
authors.forename: Edith J M
authors.initials: EJ
authors.lastname: Feskens
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
mesh_terms: D017668:Age of Onset; D015992:Body Mass Index; D049628:Body Size; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005190:Family; D014644:Genetic Variation; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D015201:Meta-Analysis as Topic; D008875:Middle Aged; D016017:Odds Ratio; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins