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Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia

Rung, Johan; Cauchi, Stephane; Albrechtsen, Anders; Shen, Lishuang; Rocheleau, Ghislain; Cavalcanti-Proenca, Christine; Bacot, Francois; Balkau, Beverley; Belisle, Alexandre and Borch-Johnsen, Knut, et al. (2009) In Nature Genetics 41(10). p.89-1110
Abstract
Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 x 10(-12), OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with... (More)
Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 x 10(-12), OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies. (Less)
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@article{2888b8af-c8be-4312-a929-162af8760526,
  abstract     = {Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 x 10(-12), OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.},
  author       = {Rung, Johan and Cauchi, Stephane and Albrechtsen, Anders and Shen, Lishuang and Rocheleau, Ghislain and Cavalcanti-Proenca, Christine and Bacot, Francois and Balkau, Beverley and Belisle, Alexandre and Borch-Johnsen, Knut and Charpentier, Guillaume and Dina, Christian and Durand, Emmanuelle and Elliott, Paul and Hadjadj, Samy and Jaervelin, Marjo-Riitta and Laitinen, Jaana and Lauritzen, Torsten and Marre, Michel and Mazur, Alexander and Meyre, David and Montpetit, Alexandre and Pisinger, Charlotta and Posner, Barry and Poulsen, Pernille and Pouta, Anneli and Prentki, Marc and Ribel-Madsen, Rasmus and Ruokonen, Aimo and Sandbaek, Anelli and Serre, David and Tichet, Jean and Vaxillaire, Martine and Wojtaszewski, Jorgen F. P. and Vaag, Allan and Hansen, Torben and Polychronakos, Constantin and Pedersen, Oluf and Froguel, Philippe and Sladek, Robert},
  issn         = {1546-1718},
  language     = {eng},
  number       = {10},
  pages        = {89--1110},
  publisher    = {Nature Publishing Group},
  series       = {Nature Genetics},
  title        = {Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia},
  url          = {http://dx.doi.org/10.1038/ng.443},
  volume       = {41},
  year         = {2009},
}