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

B Guigas, JED van Weenen, N van Leeuwen, AM Simonis-Bik, TW van Haeften, G Nijpels, JJ Houwing-Duistermaat, M Beekman, J Deelen, LM Havekes, BWJH Penninx, N Vogelzangs, E van Riet, Abbas Dehghan, Bert Hofman, JCM Witteman, André Uitterlinden, N Grarup, T Jorgensen, DR WitteT Lauritzen, T Hansen, O Pedersen, J Hottenga, JA Romijn, M Diamant, MHH Kramer, RJ Heine, G Willemsen, JM Dekker, EM Eekhoff, H Pijl, EJ de Geus, PE (Eline) Slagboom, LM 't Hart

Research output: Contribution to journalArticleAcademicpeer-review

16 Citations (Scopus)


Aims Modulation of dopamine receptor D2 (DRD2) activity affects insulin secretion in both rodents and isolated pancreatic beta-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
Pages (from-to)1001-1008
Number of pages8
JournalDiabetic Medicine
Issue number8
Publication statusPublished - 2014

Research programs

  • EMC MM-01-39-09-A
  • EMC NIHES-01-64-01


Dive into the research topics of 'Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility'. Together they form a unique fingerprint.

Cite this