1. Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and type 2 diabetes susceptibility.
- Author
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Guigas B, de Leeuw van Weenen JE, van Leeuwen N, Simonis-Bik AM, van Haeften TW, Nijpels G, Houwing-Duistermaat JJ, Beekman M, Deelen J, Havekes LM, Penninx BW, Vogelzangs N, van 't Riet E, Dehghan A, Hofman A, Witteman JC, Uitterlinden AG, Grarup N, Jørgensen T, Witte DR, Lauritzen T, Hansen T, Pedersen O, Hottenga J, Romijn JA, Diamant M, Kramer MH, Heine RJ, Willemsen G, Dekker JM, Eekhoff EM, Pijl H, de Geus EJ, Slagboom PE, and 't Hart LM
- Subjects
- Alleles, Case-Control Studies, Cohort Studies, Denmark, Diabetes Mellitus, Type 2 blood, Diabetes Mellitus, Type 2 metabolism, Female, Gene Frequency, Genetic Association Studies, Genetic Loci, Humans, Hyperglycemia blood, Hyperglycemia genetics, Hyperglycemia metabolism, Insulin blood, Insulin Secretion, Male, Middle Aged, Netherlands, Protein Serine-Threonine Kinases genetics, Protein Serine-Threonine Kinases metabolism, Receptors, Dopamine D2 metabolism, Sex Characteristics, Diabetes Mellitus, Type 2 genetics, Genetic Predisposition to Disease, Insulin metabolism, Insulin Resistance, Insulin-Secreting Cells metabolism, Polymorphism, Single Nucleotide, Receptors, Dopamine D2 genetics
- Abstract
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*10⁴) 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*10⁴) 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., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)
- Published
- 2014
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