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- Title
Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility.
- Authors
Guigas, B.; Leeuw van Weenen, J. E.; Leeuwen, N.; Simonis‐Bik, A. M.; Haeften, T. W.; Nijpels, G.; Houwing‐Duistermaat, J. J.; Beekman, M.; Deelen, J.; Havekes, L. M.; Penninx, B. W. J. H.; Vogelzangs, N.; ‘t Riet, E.; Dehghan, A.; Hofman, A.; Witteman, J. C.; Uitterlinden, A. G.; Grarup, N.; Jørgensen, T.; Witte, D. R.
- 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*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.
- Subjects
TYPE 2 diabetes diagnosis; GENETICS of type 2 diabetes; HYPERGLYCEMIA; BLOOD testing; BLOOD sugar; CELL receptors; CONFIDENCE intervals; DOPAMINE; GENES; GENETICS; TYPE 2 diabetes; SEXUAL intercourse; DATA analysis; BODY mass index; DIAGNOSIS
- Publication
Diabetic Medicine, 2014, Vol 31, Issue 8, p1001
- ISSN
0742-3071
- Publication type
Article
- DOI
10.1111/dme.12464