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E23K with type 2 diabetes are both robustly observed in these 9,000 subjects, including an additional (previously unpublished) confirmation of Kir6.2 E23K and type 2 diabetes in the Polish and North American samples (combined OR 1.15 [1.05-1.26], P = 0.001).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: Jose C Florez, Marketa Sjögren, Noël Burtt, Marju Orho-Melander, Steve Schayer, Maria Sun, Peter Almgren, Ulf Lindblad, Tiinamaija Tuomi, Daniel Gaudet, Thomas J Hudson, Mark J Daly, Kristin G Ardlie, Joel N Hirschhorn, David Altshuler, Leif Groop
• Journal: Diabetes (Diabetes) Vol. 53 Issue 12 Pg. 3313-8 (Dec 2004) ISSN: 0012-1797 [Print] United States
• PMID: 15561965 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• IRS1 protein, human
• Insulin Receptor Substrate Proteins
• Phosphoproteins

Topics

• Amino Acid Substitution
• Diabetes Mellitus, Type 2 (genetics)
• Humans
• Insulin Receptor Substrate Proteins
• Phenotype
• Phosphoproteins (genetics)
• Polymorphism, Single Nucleotide (genetics)
• Scandinavian and Nordic Countries
• Siblings
• White People (genetics)