Sex-specific effects of naturally occurring variants in the dopamine receptor D2 locus on insulin secretion and type 2 diabetes susceptibility.
OBJECTIVE
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*10⁴) 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*10⁴) but again not in men (P = 0.34).


CONCLUSIONS
The present data identify DRD2/ANKK1 as a potential sex-specific type 2 diabetes susceptibility gene.
Department of Molecular Cell Biology, Leiden University Medical Centre, Leiden, The Netherlands; Department of Parasitology, Leiden University Medical Centre, Leiden, The Netherlands.
B
B
Guigas
J E
JE
de Leeuw van Weenen
N
N
van Leeuwen
A M
AM
Simonis-Bik
T W
TW
van Haeften
G
G
Nijpels
J J
JJ
Houwing-Duistermaat
M
M
Beekman
J
J
Deelen
L M
LM
Havekes
B W J H
BW
Penninx
N
N
Vogelzangs
E
E
van 't Riet
A
A
Dehghan
A
A
Hofman
J C
JC
Witteman
A G
AG
Uitterlinden
N
N
Grarup
T
T
Jørgensen
D R
DR
Witte
T
T
Lauritzen
T
T
Hansen
O
O
Pedersen
J
J
Hottenga
J A
JA
Romijn
M
M
Diamant
M H H
MH
Kramer
R J
RJ
Heine
G
G
Willemsen
J M
JM
Dekker
E M
EM
Eekhoff
H
H
Pijl
E J
EJ
de Geus
P E
PE
Slagboom
L M
LM
't Hart
D000483:Alleles; D016022:Case-Control Studies; D015331:Cohort Studies; D003718:Denmark; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D006943:Hyperglycemia / Q000097:blood / Q000235:genetics / Q000378:metabolism; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D050417:Insulin-Secreting Cells / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009426:Netherlands; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000235:genetics* / Q000378:metabolism; D012727:Sex Characteristics
C581293:DRD2 protein, human; D007328:Insulin; D017448:Receptors, Dopamine D2; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases