Sex‐specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility. Issue 8 (2nd May 2014)

• Record Type: Journal Article
• Authors: 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.;
• Is Part Of: Diabetic medicine. Volume 31:Issue 8(2014:Aug.)
• Page Start: 1001
• Page End: 1008
• Publication Date: 2014-05-02
• Subjects: Diabetes -- Periodicals; 616.462
• DOI: 10.1111/dme.12464
• Languages: English
• ISSNs: 0742-3071

Abstract

<abstract abstract-type="main" id="dme12464-abs-0001"> <title>Abstract</title> <sec id="dme12464-sec-0001" sec-type="section"> <title>Aims</title> <p>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 <italic>DRD2/ANKK1</italic> locus may affect susceptibility to Type 2 diabetes in humans.</p> </sec> <sec id="dme12464-sec-0002" sec-type="section"> <title>Methods</title> <p>Four potentially functional variants in the coding region of the <italic>DRD2/ANKK1</italic> 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 <italic>DRD2</italic> polymorphisms have been previously reported, we also performed a gender‐stratified analysis.</p> </sec> <sec id="dme12464-sec-0003" sec-type="section"> <title>Results</title> <p>rs1800497 at the <italic>DRD2/ANKK1</italic> locus was associated with a significantly increased risk for Type 2 diabetes in women (odds ratio 1.14 (1.06–1.23); <italic>P </italic>=<italic> </italic>4.1*10<sup>−4</sup>) but not in men (odds ratio 1.00 (95% CI 0.93–1.07); <italic>P </italic>=<italic> </italic>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 (<italic>P </italic>=<italic> </italic>5.5*10<sup>−4</sup>) but again not in men (<italic>P </italic>=<italic> </italic>0.34).</p> </sec> <sec id="dme12464-sec-0004" sec-type="section"> <title>Conclusion</title> <p>The present data identify <italic>DRD2/ANKK1</italic> as a potential sex‐specific Type 2 diabetes susceptibility gene.</p> </sec> </abstract>