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

Nat Genet. 2009 Oct;41(10):1110-5. doi: 10.1038/ng.443. Epub 2009 Sep 6.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alleles
  • Biopsy
  • Diabetes Mellitus, Type 2 / complications
  • Diabetes Mellitus, Type 2 / genetics*
  • Diabetes Mellitus, Type 2 / metabolism
  • Diabetes Mellitus, Type 2 / pathology
  • European Continental Ancestry Group / genetics
  • Female
  • Genome, Human*
  • Genome-Wide Association Study
  • Humans
  • Hyperinsulinism / complications
  • Hyperinsulinism / genetics*
  • Hyperinsulinism / metabolism
  • Hyperinsulinism / pathology
  • Insulin Receptor Substrate Proteins / genetics*
  • Insulin Resistance*
  • Male
  • Middle Aged
  • Muscle, Skeletal / metabolism
  • Muscle, Skeletal / pathology
  • Phosphatidylinositol 3-Kinases / metabolism
  • Polymorphism, Single Nucleotide*

Substances

  • IRS1 protein, human
  • Insulin Receptor Substrate Proteins
  • Phosphatidylinositol 3-Kinases