Genetic variation in the dopamine D4 receptor (DRD4) gene and smoking cessation: follow-up of a randomised clinical trial of transdermal nicotine patch.
Smokers of European ancestry (n=720) who participated in a double-blind, randomised, placebo-controlled trial of transdermal nicotine replacement therapy, were genotyped for two functional polymorphisms (variable number of tandem repeats (VNTR) and a C to T transition at position -521 (C-521T)) in the dopamine D4 receptor gene (DRD4) gene. Logistic regression models of abstinence at 12- and 26-week follow-ups were carried out separately for each polymorphism. For the DRD4 VNTR models, the main effect of treatment was significant at both 12-week (P=0.001) and 26-week (P=0.006) follow-ups, indicating an increased likelihood of successful cessation on active nicotine replacement therapy transdermal patch relative to placebo. The main effect of DRD4 VNTR genotype was associated with abstinence at 12-week follow-up (P=0.034), with possession of one or more copies of the long allele associated with reduced likelihood of cessation (17 vs 23%), but this effect was not observed at 26-week follow-up. For the DRD4 C-521T models, no main effect or interaction terms involving genotype were retained in the models at either 12- or 26-week follow-up. These data are consistent with observations from studies of the DRD2 gene that genetic variants related to relatively decreased dopaminergic tone in the mesocorticolimbic system are associated with increased risk for relapse to smoking following a cessation attempt.
David
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SP
Brown Medical School/Memorial Hospital of Rhode Island, Pawtucket, RI, USA. Sean_David@Brown.Edu
Munafò
M R
MR
Murphy
M F G
MF
Proctor
M
M
Walton
R T
RT
Johnstone
E C
EC
D000279:Administration, Cutaneous; D000328:Adult; D004311:Double-Blind Method; D005091:Exons; D005260:Female; D005500:Follow-Up Studies; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D018598:Minisatellite Repeats; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D016017:Odds Ratio; D011110:Polymorphism, Genetic; D050638:Receptors, Dopamine D4 / Q000235:genetics* / Q000378:metabolism; D018570:Risk Assessment; D012307:Risk Factors; D012907:Smoking / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D016540:Smoking Cessation; D013997:Time Factors; D017211:Treatment Failure; D016896:Treatment Outcome; D044465:White People / Q000235:genetics
C493599:DRD4 protein, human; D018722:Nicotinic Agonists; D050638:Receptors, Dopamine D4; D009538:Nicotine