HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Florez, J. C. Articles by Groop, L. Search for Related Content PubMed PubMed Citation Articles by Florez, J. C. Articles by Groop, L. Social Bookmarking                What's this?

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

¹ Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts
² Diabetes Unit, Massachusetts General Hospital, Boston, Massachusetts
³ Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts
⁴ Department of Medicine, Harvard Medical School, Boston, Massachusetts
⁵ Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden
⁶ Department of Community Medicine, University Hospital MAS, Lund University, Malmö, Sweden
⁷ Department of Medicine, Helsinki University Central Hospital; Folkhalsan Genetic Institute, Folkhalsan Research Center; and Research Program for Molecular Medicine, University of Helsinki, Helsinki, Finland
⁸ University of Montreal Community Genomic Center, Chicoutimi Hospital, Quebec, Canada
⁹ McGill University and Genome Quebec Innovation Centre, Montreal, Canada
¹⁰ Genomics Collaborative, Cambridge, Massachusetts
¹¹ Department of Genetics, Harvard Medical School, Boston, Massachusetts
¹² Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts

The insulin receptor substrate (IRS)-1 is an important component of the insulin signal transduction cascade. Several reports suggest that a GlyArg 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 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.

Leif Groop, Department of Endocrinology, University Hospital MAS, Lund University, Malmö, Sweden. E-mail: leif.groop{at}endo.mas.lu.se

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. C. Florez, R. Saxena, W. Winckler, N. P. Burtt, P. Almgren, K. Bengtsson Bostrom, T. Tuomi, D. Gaudet, K. G. Ardlie, M. J. Daly, et al. The Kruppel-Like Factor 11 (KLF11) Q62R Polymorphism Is Not Associated With Type 2 Diabetes in 8,676 People Diabetes, December 1, 2006; 55(12): 3620 - 3624. [Abstract] [Full Text] [PDF]

				H. N. Lyon, J. C. Florez, T. Bersaglieri, R. Saxena, W. Winckler, P. Almgren, U. Lindblad, T. Tuomi, D. Gaudet, X. Zhu, et al. Common Variants in the ENPP1 Gene Are Not Reproducibly Associated With Diabetes or Obesity Diabetes, November 1, 2006; 55(11): 3180 - 3184. [Abstract] [Full Text] [PDF]

				R. Saxena, L. Gianniny, N. P. Burtt, V. Lyssenko, C. Giuducci, M. Sjogren, J. C. Florez, P. Almgren, B. Isomaa, M. Orho-Melander, et al. Common Single Nucleotide Polymorphisms in TCF7L2 Are Reproducibly Associated With Type 2 Diabetes and Reduce the Insulin Response to Glucose in Nondiabetic Individuals. Diabetes, October 1, 2006; 55(10): 2890 - 2895. [Abstract] [Full Text] [PDF]

				S. K. Das, W. S. Chu, T. C. Hale, X. Wang, R. L. Craig, H. Wang, A. R. Shuldiner, P. Froguel, P. Deloukas, M. I. McCarthy, et al. Polymorphisms in the Glucokinase-Associated, Dual-Specificity Phosphatase 12 (DUSP12) Gene Under Chromosome 1q21 Linkage Peak Are Associated With Type 2 Diabetes Diabetes, September 1, 2006; 55(9): 2631 - 2639. [Abstract] [Full Text] [PDF]

				G. Sesti, L. Perego, M. Cardellini, F. Andreozzi, C. Ricasoli, P. Vedani, V. Guzzi, M. Marchi, M. Paganelli, G. Ferla, et al. Impact of Common Polymorphisms in Candidate Genes for Insulin Resistance and Obesity on Weight Loss of Morbidly Obese Subjects after Laparoscopic Adjustable Gastric Banding and Hypocaloric Diet J. Clin. Endocrinol. Metab., September 1, 2005; 90(9): 5064 - 5069. [Abstract] [Full Text] [PDF]

				W. Winckler, N. P. Burtt, J. Holmkvist, C. Cervin, P. I.W. de Bakker, M. Sun, P. Almgren, T. Tuomi, D. Gaudet, T. J. Hudson, et al. Association of Common Variation in the HNF1{alpha} Gene Region With Risk of Type 2 Diabetes Diabetes, August 1, 2005; 54(8): 2336 - 2342. [Abstract] [Full Text] [PDF]

				C. Sweeney, M. A. Murtaugh, K. B. Baumgartner, T. Byers, A. R. Giuliano, J. S. Herrick, R. Wolff, B. J. Caan, and M. L. Slattery Insulin-Like Growth Factor Pathway Polymorphisms Associated with Body Size in Hispanic and Non-Hispanic White Women Cancer Epidemiol. Biomarkers Prev., July 1, 2005; 14(7): 1802 - 1809. [Abstract] [Full Text] [PDF]

				J. C. Florez, C. M. Agapakis, N. P. Burtt, M. Sun, P. Almgren, L. Rastam, T. Tuomi, D. Gaudet, T. J. Hudson, M. J. Daly, et al. Association Testing of the Protein Tyrosine Phosphatase 1B Gene (PTPN1) With Type 2 Diabetes in 7,883 People Diabetes, June 1, 2005; 54(6): 1884 - 1891. [Abstract] [Full Text] [PDF]

				W. Winckler, R. R. Graham, P. I.W. de Bakker, M. Sun, P. Almgren, T. Tuomi, D. Gaudet, T. J. Hudson, K. G. Ardlie, M. J. Daly, et al. Association Testing of Variants in the Hepatocyte Nuclear Factor 4{alpha} Gene With Risk of Type 2 Diabetes in 7,883 People Diabetes, March 1, 2005; 54(3): 886 - 892. [Abstract] [Full Text] [PDF]

				E. Zeggini, J. Parkinson, S. Halford, K. R. Owen, T. M. Frayling, M. Walker, G. A. Hitman, J. C. Levy, M. J. Sampson, E. J.M. Feskens, et al. Association Studies of Insulin Receptor Substrate 1 Gene (IRS1) Variants in Type 2 Diabetes Samples Enriched for Family History and Early Age of Onset Diabetes, December 1, 2004; 53(12): 3319 - 3322. [Abstract] [Full Text] [PDF]