New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk

Nat Genet. 2010 Feb;42(2):105-16. doi: 10.1038/ng.520. Epub 2010 Jan 17.

Abstract

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes.

MeSH terms

  • Adolescent
  • Adult
  • Alleles
  • Blood Glucose / genetics*
  • Blood Glucose / metabolism*
  • Child
  • DNA Copy Number Variations / genetics
  • Databases, Genetic
  • Diabetes Mellitus, Type 2 / genetics*
  • Fasting / blood*
  • Gene Expression Regulation
  • Genetic Loci / genetics*
  • Genetic Predisposition to Disease*
  • Genome-Wide Association Study
  • Homeostasis / genetics*
  • Humans
  • Meta-Analysis as Topic
  • Polymorphism, Single Nucleotide / genetics
  • Quantitative Trait Loci / genetics
  • Quantitative Trait, Heritable
  • Reproducibility of Results

Substances

  • Blood Glucose

Grant support