Print Email Facebook Twitter Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility Title Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility Author Guigas, B. de Leeuw van Weenen, J.E. van Leeuwen, N. Simonis-Bik, A.M. van Haeften, T.W. Nijpels, G. Houwing-Duistermaat, J.J. Beekman, M. Deelen, J. Havekes, L.M. Penninx, B.W.J.H. Vogelzangs, N. van 't Riet, E. 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. de Geus, E.J. Slagboom, P.E. 't Hart, L.M. Publication year 2014 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 Subject LifeMHR - Metabolic Health ResearchELSS - Earth, Life and Social SciencesBiomedical InnovationBiologyHealthy LivingDopamine 2 receptorGlucoseInsulinAdultAgedCohort analysisControlled studyFemaleGene locusGenetic associationGenetic codeGenetic riskGenetic susceptibilityGenetic variabilityGenotype HumanInsulin releaseMajor clinical studyMaleNon insulin dependent diabetes mellitusPancreas islet beta cellPopulation based case control studyRandomized controlled trialSex differenceSingle nucleotide polymorphism To reference this document use: http://resolver.tudelft.nl/uuid:14bdaec3-2e64-488b-83c8-769f16194f53 DOI https://doi.org/10.1111/dme.12464 TNO identifier 513411 ISSN 1464-5491 Source Diabetic Medicine, 31 (8), 1001-1008 Document type article Files To receive the publication files, please send an e-mail request to TNO Library.