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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
Author(s) -
Guigas B.,
Leeuw van Weenen J. E.,
Leeuwen N.,
SimonisBik A. M.,
Haeften T. W.,
Nijpels G.,
HouwingDuistermaat J. J.,
Beekman M.,
Deelen J.,
Havekes L. M.,
Penninx B. W. J. H.,
Vogelzangs N.,
‘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.,
Geus E. J.,
Slagboom P. E.,
‘t Hart L. M.
Publication year - 2014
Publication title -
diabetic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.474
H-Index - 145
eISSN - 1464-5491
pISSN - 0742-3071
DOI - 10.1111/dme.12464
Subject(s) - endocrinology , type 2 diabetes , medicine , locus (genetics) , single nucleotide polymorphism , diabetes mellitus , insulin , odds ratio , biology , genetics , genotype , gene
Aims Modulation of dopamine receptor D2 ( DRD 2) activity affects insulin secretion in both rodents and isolated pancreatic β‐cells. We hypothesized that single nucleotide polymorphisms in the DRD 2/ ANKK 1 locus may affect susceptibility to Type 2 diabetes in humans. Methods Four potentially functional variants in the coding region of the DRD 2/ ANKK 1 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 DRD 2/ ANKK 1 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 DRD 2/ ANKK 1 as a potential sex‐specific Type 2 diabetes susceptibility gene.