Association Testing in 9,000 People Fails to Confirm the Association of the Insulin Receptor Substrate-1 G972R Polymorphism With Type 2 Diabetes

  1. Jose C. Florez1234,
  2. Marketa Sjögren5,
  3. Noël Burtt3,
  4. Marju Orho-Melander5,
  5. Steve Schayer3,
  6. Maria Sun13,
  7. Peter Almgren5,
  8. Ulf Lindblad6,
  9. Tiinamaija Tuomi7,
  10. Daniel Gaudet8,
  11. Thomas J. Hudson9,
  12. Mark J. Daly3,
  13. Kristin G. Ardlie10,
  14. Joel N. Hirschhorn31112,
  15. David Altshuler123411 and
  16. Leif Groop5
  1. 1Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
  2. 2Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts
  3. 3Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
  4. 4Department of Medicine, Harvard Medical School, Boston, Massachusetts
  5. 5Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
  6. 6Department of Community Medicine, University Hospital MAS, Lund University, Malmö, Sweden
  7. 7Department of Medicine, Helsinki University Central Hospital; Folkhalsan Genetic Institute, Folkhalsan Research Center; and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
  8. 8University of Montreal Community Genomic Center, Chicoutimi Hospital, Quebec, Canada
  9. 9McGill University and Genome Quebec Innovation Centre, Montreal, Canada
  10. 10Genomics Collaborative, Cambridge, Massachusetts
  11. 11Department of Genetics, Harvard Medical School, Boston, Massachusetts
  12. 12Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts
  1. Address correspondence and reprint requests to David Altshuler, Department of Molecular Biology, Massachusetts General Hospital, Boston, MA 02114. E-mail: altshuler{at}molbio.mgh.harvard.edu
  2. Leif Groop, Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden. E-mail: leif.groop{at}endo.mas.lu.se

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 γ 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.

Footnotes

  • D.A. and L.G. jointly supervised this project.

    In the past, D.A. has been on an advisory panel for and received consulting fees from Genomics Collaborative.

    • Accepted August 23, 2004.
    • Received July 9, 2004.
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  1. doi: 10.2337/diabetes.53.12.3313 Diabetes December 2004 vol. 53 no. 12 3313-3318
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