Association of GCKR rs780094, alone or in combination with GCK rs1799884, with type 2 diabetes and related traits in a Han Chinese population

Diabetologia. 2009 May;52(5):834-43. doi: 10.1007/s00125-009-1290-2. Epub 2009 Feb 25.

Abstract

Aims/hypothesis: The GCKR rs780094 and GCK rs1799884 polymorphisms have been reported to be associated with dyslipidaemia and type 2 diabetes in white Europeans. The aim of this study was to replicate these associations in Han Chinese individuals and to identify the potential mechanisms underlying these associations.

Methods: The single nucleotide polymorphisms rs780094 and rs1799884 were genotyped in a population-based sample of Han Chinese individuals (n = 3,210) and tested for association with risk of type 2 diabetes and related phenotypes.

Results: The GCKR rs780094 A allele was marginally associated with reduced risk of type 2 diabetes (OR 0.85, 95% CI 0.73-1.00, p value under an additive model [p((add))] = 0.05) and significantly associated with reduced risk of impaired fasting glucose (IFG) or type 2 diabetes (OR 0.86, 95% CI 0.77-0.96, p([add]) = 0.0032). It was also significantly associated with decreased fasting glucose and increased HOMA of beta cell function (HOMA-B) and fasting triacylglycerol levels (p([add]) = 0.0169-5.3 x 10(-6)), but not with HOMA of insulin sensitivity (HOMA-S). The associations with type 2 diabetes and IFG remained significant after adjustment for BMI, while adjustment for HOMA-B abolished the associations. The GCKR rs780094 was also associated with obesity and BMI, independently of its association with type 2 diabetes. The GCK rs1799884 A allele was significantly associated with decreased HOMA-B (p([add]) = 0.0005), but not with type 2 diabetes or IFG. Individuals with increasing numbers of risk alleles for both variants had significantly lower HOMA-B (p([add]) = 5.8 x 10(-5)) in the combined analysis.

Conclusions/interpretation: Consistent with observations in white Europeans, the GCKR rs780094 polymorphism contributes to the risk of type 2 diabetes and dyslipidaemia in Han Chinese individuals. In addition, we showed that the effect on type 2 diabetes is probably mediated through impaired beta cell function rather than through obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Aged
  • Asian Continental Ancestry Group / genetics*
  • Body Size
  • C-Reactive Protein / metabolism
  • China
  • DNA / blood
  • DNA / genetics
  • DNA / isolation & purification
  • Diabetes Mellitus, Type 2 / epidemiology
  • Diabetes Mellitus, Type 2 / genetics*
  • European Continental Ancestry Group / genetics
  • Female
  • Genetic Variation
  • Genotype
  • Germinal Center Kinases
  • Humans
  • Insulin / blood
  • Male
  • Middle Aged
  • Obesity / epidemiology
  • Overweight / epidemiology
  • Polymorphism, Genetic*
  • Protein-Serine-Threonine Kinases / genetics*
  • Risk Factors

Substances

  • Adaptor Proteins, Signal Transducing
  • GCKR protein, human
  • Germinal Center Kinases
  • Insulin
  • C-Reactive Protein
  • DNA
  • Protein-Serine-Threonine Kinases