DRD2 genetic variation in relation to smoking and obesity in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial.
OBJECTIVE
Cigarette smoking is the leading cause of morbidity and mortality worldwide. We investigated the association between smoking behavior and genetic variations in the D2 dopamine receptor (DRD2), which mediates nicotine dependence. To assess the specificity of genetic effects, we also investigated other reward-motivated characteristics (obesity, alcohol consumption).


METHODS
Four single nucleotide polymorphisms in DRD2 were genotyped in 2374 participants selected randomly from the screening arm of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial after stratifying by sex, age, and smoking status. Smoking, obesity, and alcohol consumption were assessed by questionnaire. Single nucleotide polymorphism and haplotype associations were estimated using odds ratios (ORs) and 95% confidence intervals derived from conditional logistic regression models, adjusted for race/ethnicity.


RESULTS
DRD2 polymorphisms were associated with the risk of remaining a current smoker and obesity. Current smokers were more likely than former smokers to possess the variant TaqIA allele (rsmusical sharp1800497) in a dose-dependent model (ORCT=1.2, ORTT=1.5, P for linear trend=0.007). The DRD2 haplotype T-C-T-A [TaqIA(C/T)-957(T/C)-IVS6-83(G/T)- -50977(A/G)] was more common among current than former smokers (OR=1.3, P=0.006), particularly among heavy smokers (21+ cigarettes per day; OR=1.6, P=0.006), and was more common among obese than normal weight individuals (OR=1.4, P=0.02).


CONCLUSIONS
Genetic variation in DRD2 is a modifier of the reward-motivated characteristics, smoking and obesity. As fewer than 15% of smokers who attempt to quit are able to maintain abstinence for greater than 3 months, our results support that DRD2 is an appropriate molecular target for smoking cessation treatments. Our results further support evaluation of DRD2 antagonists for obesity therapies.
Morton
Lindsay M
LM
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, Rockville, MD 20852, USA. mortonli@mail.nih.gov
Wang
Sophia S
SS
Bergen
Andrew W
AW
Chatterjee
Nilanjan
N
Kvale
Paul
P
Welch
Robert
R
Yeager
Meredith
M
Hayes
Richard B
RB
Chanock
Stephen J
SJ
Caporaso
Neil E
NE
D000368:Aged; D000428:Alcohol Drinking / Q000235:genetics / Q000523:psychology; D015992:Body Mass Index; D005260:Female; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity / Q000235:genetics* / Q000523:psychology; D020641:Polymorphism, Single Nucleotide; D017448:Receptors, Dopamine D2 / Q000235:genetics*; D012201:Reward; D012907:Smoking / Q000235:genetics* / Q000523:psychology; D016540:Smoking Cessation; D014029:Tobacco Use Disorder / Q000235:genetics / Q000523:psychology
D017448:Receptors, Dopamine D2