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

• Published in: Diabetic medicine 2014-08, Vol.31 (8), p.1001-1008
• Main 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.
• Format: Article
• Language: English
• Subjects: Alleles; Biological and medical sciences; Case-Control Studies; Cohort Studies; Denmark; Diabetes; Diabetes Mellitus, Type 2 - blood; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Feeding. Feeding behavior; Female; Fundamental and applied biological sciences. Psychology; Gene Frequency; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Humans; Hyperglycemia - blood; Hyperglycemia - genetics; Hyperglycemia - metabolism; Insulin - blood; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Insulin-Secreting Cells - metabolism; Male; Medical sciences; Middle Aged; Netherlands; Polymorphism, Single Nucleotide; Protein-Serine-Threonine Kinases - genetics; Protein-Serine-Threonine Kinases - metabolism; Receptors, Dopamine D2 - genetics; Receptors, Dopamine D2 - metabolism; Sex Characteristics; Vertebrates: anatomy and physiology, studies on body, several organs or systems; Vertebrates: endocrinology
• ISSN: 0742-3071; 1464-5491
• DOI: 10.1111/dme.12464

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.