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- Title
Association testing in 9,000 people fails to confirm the association of the insulin receptor substrate-1 G972R polymorphism with type 2 diabetes.
- Authors
Florez, Jose C.; Sjögren, Marketa; Burtt, Noël; Orho-Melander, Marju; Schayer, Steve; Sun, Maria; Almgren, Peter; Lindblad, Ulf; Tuomi, Tiinamaija; Gaudet, Daniel; Hudson, Thomas J.; Daly, Mark J.; Ardlie, Kristin G.; Hirschhorn, Joel N.; Altshuler, David; Groop, Leif; Sjögren, Marketa; Burtt, Noël
- 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E23K with type 2 diabetes are both robustly observed in these 9,000 subjects, including an additional (previously unpublished) confirmation of Kir6.2 E23K and type 2 diabetes in the Polish and North American samples (combined OR 1.15 [1.05-1.26], P = 0.001).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.
- Subjects
SCANDINAVIA; INSULIN; CELLULAR signal transduction; DIABETES; GENOTYPE-environment interaction; PHENOTYPES; AMINO acids; SIBLINGS; CARRIER proteins; COMPARATIVE studies; GENETIC polymorphisms; RESEARCH methodology; MEDICAL cooperation; TYPE 2 diabetes; PHOSPHOPROTEINS; RESEARCH; WHITE people; EVALUATION research
- Publication
Diabetes, 2004, Vol 53, Issue 12, p3313
- ISSN
0012-1797
- Publication type
journal article
- DOI
10.2337/diabetes.53.12.3313