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Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility
| article |
2014
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| Author: |
Guigas, B.
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Leeuw van Weenen, J.E. de
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van Leeuwen, N.
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Simonis-Bik, A.M.
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Haeften, T.W. van
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Nijpels, G.
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Houwing-Duistermaat, J.J.
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Beekman, M.
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Deelen, J.
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Havekes, L.M.
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Penninx, B.W.J.H.
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Vogelzangs, N.
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Riet, E. van 't
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Dehghan, A.
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Hofman, A.
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Witteman, J.C.
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Uitterlinden, A.G.
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Grarup, N.
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Jørgensen, T.
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Witte, D.R.
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Lauritzen, T.
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Hansen, T.
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Pedersen, O.
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Hottenga, J.
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Romijn, J.A.
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Diamant, M.
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Kramer, M.H.H.
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Heine, R.J.
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Willemsen, G.
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Dekker, J.M.
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Eekhoff, E.M.
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Pijl, H.
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Geus, E.J. de
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Slagboom, P.E.
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Hart, L.M. 't
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| Keywords: |
Biology · Dopamine 2 receptor · Glucose · Insulin · Adult · Aged · Cohort analysis · Controlled study · Female · Gene locus · Genetic association · Genetic code · Genetic risk · Genetic susceptibility · Genetic variability · Genotype Human · Insulin release · Major clinical study · Male · Non insulin dependent diabetes mellitus · Pancreas islet beta cell · Population based case control study · Randomized controlled trial · Sex difference · Single nucleotide polymorphism · Biomedical Innovation · Healthy Living · Life · MHR - Metabolic Health Research · ELSS - Earth, Life and Social Sciences
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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
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[Abstract]
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