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Free keywords:
Alleles
Case-Control Studies
Cohort Studies
Denmark
Diabetes Mellitus, Type 2/blood/*genetics/metabolism
Female
Gene Frequency
Genetic Association Studies
Genetic Loci
*Genetic Predisposition to Disease
Humans
Hyperglycemia/blood/genetics/metabolism
Insulin/blood/*metabolism
*Insulin Resistance
Insulin Secretion
Insulin-Secreting Cells/*metabolism
Male
Middle Aged
Netherlands
*Polymorphism, Single Nucleotide
Protein-Serine-Threonine Kinases/genetics/metabolism
Receptors, Dopamine D2/*genetics/metabolism
Sex Characteristics
Abstract:
AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic beta-cells. We hypothesized that single nucleotide polymorphisms in the DRD2/ANKK1 locus may affect susceptibility to type 2 diabetes in humans. METHODS: Four potentially functional variants in the coding region of the DRD2/ANKK1 locus (rs1079597, rs6275, rs6277, rs1800497) were genotyped and analysed for type 2 diabetes susceptibility in up to 25 000 people (8148 with type 2 diabetes and 17687 control subjects) from two large independent Dutch cohorts and one Danish cohort. In addition, 340 Dutch subjects underwent a 2-h hyperglycaemic clamp to investigate insulin secretion. Since sexual dimorphic associations related to DRD2 polymorphisms have been previously reported, we also performed a gender-stratified analysis. RESULTS: rs1800497 at the DRD2/ANKK1 locus was associated with a significantly increased risk for type 2 diabetes in women (odds ratio 1.14 (1.06-1.23); P = 4.1*10(4)) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); P = 0.92) or the combined group. Although rs1800497 was not associated with insulin secretion, we did find another single nucleotide polymorphism in this locus, rs6275, to be associated with increased first-phase glucose-stimulated insulin secretion in women (P = 5.5*10(4)) but again not in men (P = 0.34). CONCLUSION: The present data identify DRD2/ANKK1 as a potential sex-specific type 2 diabetes susceptibility gene.
