AIMS/HYPOTHESIS: Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants might account for the putative association signal. SUBJECTS AND METHODS: We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers in several family-based and case-control samples of European descent totalling 12,129 subjects. RESULTS: In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03-1.51, p = 0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96-1.39, p = 0.059). The combined OR was 1.20 (p = 0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits. CONCLUSIONS/ INTERPRETATION: Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent.
AIMS/HYPOTHESIS: Activation of the insulin receptor substrate-1 (IRS1) is a key initial step in the insulin signalling pathway. Despite several reports of association of the G972R polymorphism in its gene IRS1 with type 2 diabetes, we and others have not observed this association in well-powered samples. However, other nearby variants might account for the putative association signal. SUBJECTS AND METHODS: We characterised the haplotype map of IRS1 and selected 20 markers designed to capture common variations in the region. We genotyped this comprehensive set of markers in several family-based and case-control samples of European descent totalling 12,129 subjects. RESULTS: In an initial sample of 2,235 North American and Polish case-control pairs, the minor allele of the rs934167 polymorphism showed nominal evidence of association with type 2 diabetes (odds ratio [OR] 1.25, 95% CI 1.03-1.51, p = 0.03). This association showed a trend in the same direction in 7,659 Scandinavian samples (OR 1.16, 95% CI 0.96-1.39, p = 0.059). The combined OR was 1.20 (p = 0.008), but statistical correction for the number of variants examined yielded a p value of 0.086. We detected no differences across rs934167 genotypes in insulin-related quantitative traits. CONCLUSIONS/ INTERPRETATION: Our data do not support an association of common variants in IRS1 with type 2 diabetes in populations of European descent.
Authors: Paul I W de Bakker; Roman Yelensky; Itsik Pe'er; Stacey B Gabriel; Mark J Daly; David Altshuler Journal: Nat Genet Date: 2005-10-23 Impact factor: 38.330
Authors: Maria W Sun; Jennifer Y Lee; Paul I W de Bakker; Noël P Burtt; Peter Almgren; Lennart Råstam; Tiinamaija Tuomi; Daniel Gaudet; Mark J Daly; Joel N Hirschhorn; David Altshuler; Leif Groop; Jose C Florez Journal: Diabetes Date: 2006-03 Impact factor: 9.461
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 Date: 2004-12 Impact factor: 9.461
Authors: Jose C Florez; Christina M Agapakis; Noël P Burtt; Maria Sun; Peter Almgren; Lennart Råstam; Tiinamaija Tuomi; Daniel Gaudet; Thomas J Hudson; Mark J Daly; Kristin G Ardlie; Joel N Hirschhorn; Leif Groop; David Altshuler Journal: Diabetes Date: 2005-06 Impact factor: 9.461
Authors: E Reiling; B Jafar-Mohammadi; E van 't Riet; M N Weedon; J V van Vliet-Ostaptchouk; T Hansen; R Saxena; T W van Haeften; P A Arp; S Das; G Nijpels; M J Groenewoud; E C van Hove; A G Uitterlinden; J W A Smit; A D Morris; A S F Doney; C N A Palmer; C Guiducci; A T Hattersley; T M Frayling; O Pedersen; P E Slagboom; D M Altshuler; L Groop; J A Romijn; J A Maassen; M H Hofker; J M Dekker; M I McCarthy; L M 't Hart Journal: Diabetologia Date: 2009-10-22 Impact factor: 10.122