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; Torben Hansen; Oluf Borbye Pedersen; J Hottenga; J A Romijn; M Diamant; Mark 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 WitteT Lauritzen, Torben Hansen, Oluf Borbye Pedersen, J Hottenga, J A Romijn, M Diamant, Mark 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

16 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Diabetic Medicine Online
Vol/bind	31
Udgave nummer	8
Sider (fra-til)	1001-8
Antal sider	8
ISSN	1464-5491
DOI	https://doi.org/10.1111/dme.12464
Status	Udgivet - aug. 2014

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10.1111/dme.12464

Citationsformater

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 Online, 31(8), 1001-8. https://doi.org/10.1111/dme.12464

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, OB, Hottenga, J, Romijn, JA, Diamant, M, Kramer, M, 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 Online, bind 31, nr. 8, s. 1001-8. https://doi.org/10.1111/dme.12464

@article{eef6465812d244ffa129fc73de09193f,

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.",

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 Torben Hansen and Pedersen, {Oluf Borbye} and J Hottenga and Romijn, {J A} and M Diamant and Mark Kramer 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}",

note = "{\textcopyright} 2014 The Authors. Diabetic Medicine {\textcopyright} 2014 Diabetes UK.",

year = "2014",

month = aug,

doi = "10.1111/dme.12464",

language = "English",

volume = "31",

pages = "1001--8",

journal = "Diabetic Medicine Online",

issn = "1464-5491",

publisher = "Wiley-Blackwell Publishing Ltd",

number = "8",

}

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, Torben

AU - Pedersen, Oluf Borbye

AU - Hottenga, J

AU - Romijn, J A

AU - Diamant, M

AU - Kramer, Mark

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.

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.

U2 - 10.1111/dme.12464

DO - 10.1111/dme.12464

M3 - Journal article

C2 - 24724616

SN - 1464-5491

VL - 31

SP - 1001

EP - 1008

JO - Diabetic Medicine Online

JF - Diabetic Medicine Online

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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