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Diabetic Medicine

Year: 2014  |  Volume: 31  |  Issue: 8  |  Page No.: 1001 - 1008

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

B. Guigas, J. E. de Leeuw van Weenen, N. van Leeuwen, A. M. Simonis-Bik, T. W. van Haeften, G. Nijpels, J. J. Houwing-Duistermaat, M. Beekman, J. Deelen, L. M. Havekes, B. W. J. H. Penninx, N. Vogelzangs, E. van t Riet, A. Dehghan, A. Hofman, J. C. Witteman, A. G. Uitterlinden, N. Grarup, T. Jorgensen, D. R. Witte, T. Lauritzen, T. Hansen, O. Pedersen, J. Hottenga, J. A. Romijn, M. Diamant, M. H. H. Kramer, R. J. Heine, G. Willemsen, J. M. Dekker, E. M. Eekhoff, H. Pijl, E. J. de Geus, P. E. Slagboom and L. M. t Hart



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.


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.


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); = 4.1*10−4) but not in men (odds ratio 1.00 (95% CI 0.93-1.07); = 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 (= 5.5*10−4) but again not in men (= 0.34).


The present data identify DRD2/ANKK1 as a potential sex-specific Type 2 diabetes susceptibility gene.

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