Abstract
AIMS: Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic β-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*10⁴) 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*10⁴) 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.
Original language | English |
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Journal | Diabetic Medicine Online |
Volume | 31 |
Issue number | 8 |
Pages (from-to) | 1001-8 |
Number of pages | 8 |
ISSN | 1464-5491 |
DOIs | |
Publication status | Published - Aug 2014 |
Externally published | Yes |
Keywords
- Alleles
- Case-Control Studies
- Cohort Studies
- Denmark
- Diabetes Mellitus, Type 2
- Female
- Gene Frequency
- Genetic Association Studies
- Genetic Loci
- Genetic Predisposition to Disease
- Humans
- Hyperglycemia
- Insulin
- Insulin Resistance
- Insulin-Secreting Cells
- Male
- Middle Aged
- Netherlands
- Polymorphism, Single Nucleotide
- Protein-Serine-Threonine Kinases
- Receptors, Dopamine D2
- Sex Characteristics