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

B. Guigas; J. E. de Leeuw van Weenen; N. van Leeuwen; A. M. Simonis-Bik; T. W. van Haeften; G. Nijpels; J. J. Houwing-Duistermaat; M. Beekman; J. Deelen; L. M. Havekes; B. W.J.H. Penninx; N. Vogelzangs; E. van 't Riet; A. Dehghan; A. Hofman; J. C. Witteman; A. G. Uitterlinden; N. Grarup; T. Jørgensen; D. R. Witte; T. Lauritzen; T. Hansen; O. Pedersen; J. Hottenga; J. A. Romijn; M. Diamant; M. H.H. Kramer; R. J. Heine; G. Willemsen; J. M. Dekker; E. M. Eekhoff; H. Pijl; E. J. de Geus; P. E. Slagboom; L. M. 't Hart

doi:10.1111/dme.12464

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

B. Guigas^*
, J. E. de Leeuw van Weenen
, N. van Leeuwen
, A. M. Simonis-Bik
, T. W. van Haeften
, G. Nijpels
, J. J. Houwing-Duistermaat
, M. Beekman
, J. Deelen
, L. M. Havekes
, B. W.J.H. Penninx
, N. Vogelzangs
, E. van 't Riet
, A. Dehghan
, A. Hofman
, J. C. Witteman
, A. G. Uitterlinden
, N. Grarup
, T. Jørgensen
, D. R. Witte

T. Lauritzen, T. Hansen, O. Pedersen, J. Hottenga, J. A. Romijn, M. Diamant, M. H.H. Kramer, R. J. Heine, G. Willemsen, J. M. Dekker, E. M. Eekhoff, H. Pijl, E. J. de Geus, P. E. Slagboom, L. M. 't Hart

^*Corresponding author for this work

Leiden University
VU University Medical Center
Utrecht University
Vrije Universiteit (VU)
Netherlands Organisation for Applied Scientific Research
Erasmus University Rotterdam
Netherlands Genomics Initiative
University of Copenhagen
Novo Nordisk Foundation
Aarhus University
University of Southern Denmark
Vrije Universiteit Amsterdam
Eli Lilly

Research output: Contribution to journal › Article › peer-review

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*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.

Original language	English
Pages (from-to)	1001-1008
Number of pages	8
Journal	Diabetic Medicine
Volume	31
Issue number	8
DOIs	https://doi.org/10.1111/dme.12464
Publication status	Published - Aug 2014
Externally published	Yes

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10.1111/dme.12464

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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., ... 't Hart, L. M. (2014). Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility. Diabetic Medicine, 31(8), 1001-1008. https://doi.org/10.1111/dme.12464

@article{559e93bd8ecc46b89fded4b28968a96e,

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

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*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.",

author = "B. Guigas and \{de Leeuw van Weenen\}, \{J. E.\} and \{van Leeuwen\}, N. and Simonis-Bik, \{A. M.\} and \{van Haeften\}, \{T. W.\} and G. Nijpels and Houwing-Duistermaat, \{J. J.\} and M. Beekman and J. Deelen and Havekes, \{L. M.\} and Penninx, \{B. W.J.H.\} and N. Vogelzangs and \{van 't Riet\}, E. and A. Dehghan and A. Hofman and Witteman, \{J. C.\} and Uitterlinden, \{A. G.\} and N. Grarup and T. J{\o}rgensen and Witte, \{D. R.\} and T. Lauritzen and T. Hansen and O. Pedersen and J. Hottenga and Romijn, \{J. A.\} and M. Diamant and Kramer, \{M. H.H.\} and Heine, \{R. J.\} and G. Willemsen and Dekker, \{J. M.\} and Eekhoff, \{E. M.\} and H. Pijl and \{de Geus\}, \{E. J.\} and Slagboom, \{P. E.\} and \{'t Hart\}, \{L. M.\}",

year = "2014",

month = aug,

doi = "10.1111/dme.12464",

language = "English",

volume = "31",

pages = "1001--1008",

journal = "Diabetic Medicine",

issn = "0742-3071",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "8",

}

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, BWJH, 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, MHH, Heine, RJ, Willemsen, G, Dekker, JM, Eekhoff, EM, Pijl, H, de Geus, EJ, Slagboom, PE & 't Hart, LM 2014, 'Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility', Diabetic Medicine, vol. 31, no. 8, pp. 1001-1008. https://doi.org/10.1111/dme.12464

TY - JOUR

T1 - Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and Type 2 diabetes susceptibility

AU - Guigas, B.

AU - de Leeuw van Weenen, J. E.

AU - van Leeuwen, N.

AU - Simonis-Bik, A. M.

AU - van Haeften, T. W.

AU - Nijpels, G.

AU - Houwing-Duistermaat, J. J.

AU - Beekman, M.

AU - Deelen, J.

AU - Havekes, L. M.

AU - Penninx, B. W.J.H.

AU - Vogelzangs, N.

AU - van 't Riet, E.

AU - Dehghan, A.

AU - Hofman, A.

AU - Witteman, J. C.

AU - Uitterlinden, A. G.

AU - Grarup, N.

AU - Jørgensen, T.

AU - Witte, D. R.

AU - Lauritzen, T.

AU - Hansen, T.

AU - Pedersen, O.

AU - Hottenga, J.

AU - Romijn, J. A.

AU - Diamant, M.

AU - Kramer, M. H.H.

AU - Heine, R. J.

AU - Willemsen, G.

AU - Dekker, J. M.

AU - Eekhoff, E. M.

AU - Pijl, H.

AU - de Geus, E. J.

AU - Slagboom, P. E.

AU - 't Hart, L. M.

PY - 2014/8

Y1 - 2014/8

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84904347822

U2 - 10.1111/dme.12464

DO - 10.1111/dme.12464

M3 - Article

C2 - 24724616

AN - SCOPUS:84904347822

SN - 0742-3071

VL - 31

SP - 1001

EP - 1008

JO - Diabetic Medicine

JF - Diabetic Medicine

IS - 8

ER -

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

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