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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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, Niels Grarup, Torben Jørgensen, D R Witte & 15 others T Lauritzen, Torben 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, L M 't Hart

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.

Original languageEnglish
JournalDiabetic Medicine
Volume31
Issue number8
Pages (from-to)1001-8
Number of pages8
ISSN0742-3071
DOIs
Publication statusPublished - Aug 2014

ID: 120783562