title: Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes.
abstract: The insulin receptor substrate (IRS)-1 is an important component of the insulin signal transduction cascade. Several reports suggest that a Gly-->Arg change in codon 972 is associated with type 2 diabetes and related traits, and a recent meta-analysis reported a modest but nominally significant association with type 2 diabetes (odds ratio [OR] 1.25 in favor of carriers of the Arg allele [95% CI 1.05-1.48). To test the reproducibility of the model in a recent meta-analysis, we examined genotype-phenotype correlation in three large Caucasian samples (not previously reported for this variant) totaling 9,000 individuals (estimated to have >95% power to obtain a P < 0.05 for the OR of 1.25 estimated in the meta-analysis). In our combined sample, comprising 4,279 case and 3,532 control subjects, as well as 1,189 siblings discordant for type 2 diabetes, G972R was not associated with type 2 diabetes (OR 0.96 [0.84-1.10], P = 0.60). Genotype at G972R had no significant effect on various measures of insulin secretion or insulin resistance in a set of Scandinavian samples in whom we had detailed phenotypic data. In contrast, the well-documented associations of peroxisome proliferator-activated receptor gamma P12A and Kir6.2 E23K with type 2 diabetes are both robustly observed in these 9,000 subjects, including an additional (previously unpublished) confirmation of Kir6.2 E23K and type 2 diabetes in the Polish and North American samples (combined OR 1.15 [1.05-1.26], P = 0.001). Despite genotyping 9,000 people and >95% power to reproduce the estimated OR from the recent meta-analysis, we were unable to replicate the association of the IRS-1 G972R polymorphism with type 2 diabetes.
authors.affiliation: Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.forename: Marketa
authors.initials: M
authors.lastname: Sjögren
authors.forename: Noël
authors.initials: N
authors.lastname: Burtt
authors.forename: Marju
authors.initials: M
authors.lastname: Orho-Melander
authors.forename: Steve
authors.initials: S
authors.lastname: Schayer
authors.forename: Maria
authors.initials: M
authors.lastname: Sun
authors.forename: Peter
authors.initials: P
authors.lastname: Almgren
authors.forename: Ulf
authors.initials: U
authors.lastname: Lindblad
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: Mark J
authors.initials: MJ
authors.lastname: Daly
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Ardlie
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: D019943:Amino Acid Substitution; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D010641:Phenotype; D010750:Phosphoproteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012537:Scandinavian and Nordic Countries; D035781:Siblings; D044465:White People / Q000235:genetics
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; D010750:Phosphoproteins