Guigas, B3; de Leeuw van Weenen, J E4; van Leeuwen, N4; Simonis-Bik, A M4; van Haeften, T W4; Nijpels, G4; Houwing-Duistermaat, J J4; Beekman, M4; Deelen, J4; Havekes, L M4; Penninx, B W J H4; Vogelzangs, N4; van 't Riet, E4; Dehghan, A4; Hofman, A4; Witteman, J C4; Uitterlinden, A G4; Grarup, Niels6; Jørgensen, Torben7; Witte, D R4; Lauritzen, T4; Hansen, Torben6; Pedersen, O6; Hottenga, J4; Romijn, J A4; Diamant, M4; Kramer, M H H4; Heine, R J4; Willemsen, G4; Dekker, J M4; Eekhoff, E M4; Pijl, H4; de Geus, E J4; Slagboom, P E4; 't Hart, L M4
1 Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet2 Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet3 Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands; Department of Parasitology, Leiden University Medical Centre, Leiden, The Netherlands.4 unknown5 Department of Public Health, Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet6 Section for Metabolic Genetics, The Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, Københavns Universitet7 Department of Public Health, Department of Public Health, Faculty of Health and Medical Sciences, Københavns Universitet
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.
Diabetic Medicine, 2014, Vol 31, Issue 8, p. 1001-8