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Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility

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Author: Guigas, B. · Leeuw van Weenen, J.E. de · van Leeuwen, N. · Simonis-Bik, A.M. · Haeften, T.W. van · Nijpels, G. · Houwing-Duistermaat, J.J. · Beekman, M. · Deelen, J. · Havekes, L.M. · Penninx, B.W.J.H. · Vogelzangs, N. · Riet, E. van 't · Dehghan, A. · Hofman, A. · Witteman, J.C. · Uitterlinden, A.G. · Grarup, N. · Jørgensen, T. · Witte, D.R. · Lauritzen, T. · Hansen, T. · Pedersen, O. · Hottenga, J. · Romijn, J.A. · Diamant, M. · Kramer, M.H.H. · Heine, R.J. · Willemsen, G. · Dekker, J.M. · Eekhoff, E.M. · Pijl, H. · Geus, E.J. de · Slagboom, P.E. · Hart, L.M. 't
Type:article
Date:2014
Source:Diabetic Medicine, 8, 31, 1001-1008
Identifier: 513411
doi: doi:10.1111/dme.12464
Keywords: Biology · Dopamine 2 receptor · Glucose · Insulin · Adult · Aged · Cohort analysis · Controlled study · Female · Gene locus · Genetic association · Genetic code · Genetic risk · Genetic susceptibility · Genetic variability · Genotype Human · Insulin release · Major clinical study · Male · Non insulin dependent diabetes mellitus · Pancreas islet beta cell · Population based case control study · Randomized controlled trial · Sex difference · Single nucleotide polymorphism · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences

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. What's new?: The rs1800497 single nucleotide polymorphism at the DRD2/ANKK1 locus was associated with a significantly increased risk for Type 2 diabetes in women but not in men. The rs6275 single nucleotide polymorphism in the DRD2 gene is associated with increased first-phase glucose-stimulated insulin secretion in women only. Our data identify DRD2/ANKK1 as a potential sex-specific Type 2 diabetes susceptibility gene. © 2014 Diabetes UK. Chemicals/CAS: glucose, 50-99-7, 84778-64-3; insulin, 9004-10-8