Influence of a dopamine pathway additive genetic efficacy score on smoking cessation: results from two randomized clinical trials of bupropion.
OBJECTIVE
To evaluate the associations of treatment and an additive genetic efficacy score (AGES) based on dopamine functional polymorphisms with time to first smoking lapse and point prevalence abstinence at end of treatment among participants enrolled into two randomized clinical trials of smoking cessation therapies.


METHODS
Double-blind pharmacogenetic efficacy trials randomizing participants to active or placebo bupropion. Study 1 also randomized participants to cognitive-behavioral smoking cessation treatment (CBT) or this treatment with CBT for depression. Study 2 provided standardized behavioural support.


METHODS
Two hospital-affiliated clinics (study 1), and two university-affiliated clinics (study 2).


METHODS
A total of 792 self-identified white treatment-seeking smokers aged ≥18 years smoking ≥10 cigarettes per day over the last year.


METHODS
Age, gender, Fagerström Test for Nicotine Dependence, dopamine pathway genotypes (rs1800497 [ANKK1 E713K], rs4680 [COMT V158M], DRD4 exon 3 variable number of tandem repeats polymorphism [DRD4 VNTR], SLC6A3,3' VNTR) analyzed both separately and as part of an AGES, time to first lapse and point prevalence abstinence at end of treatment.


RESULTS
Significant associations of the AGES (hazard ratio [HR] = 1.10, 95% confidence interval [CI] = 1.06-1.14, P = 0.009) and of the DRD4 VNTR (HR = 1.29, 95% CI = 1.17-1.41, P = 0.0073) were observed with time to first lapse. A significant AGES by pharmacotherapy interaction was observed (β standard error = -0.18 [0.07], P = 0.016), such that AGES predicted risk for time to first lapse only for individuals randomized to placebo.


CONCLUSIONS
A score based on functional polymorphisms relating to dopamine pathways appears to predict lapse to smoking following a quit attempt, and the association is mitigated in smokers using bupropion.
Stanford University School of Medicine, Center for Education and Research in Family and Community Medicine, Division of General Medical Disciplines, Department of Medicine, Stanford, CA, USA; SRI International, Center for Health Sciences, Menlo Park, CA, USA; Alpert Medical School of Brown University, Department of Family Medicine, Pawtucket, RI, USA.
Sean P
SP
David
David R
DR
Strong
Adam M
AM
Leventhal
Molly A
MA
Lancaster
John E
JE
McGeary
Marcus R
MR
Munafò
Andrew W
AW
Bergen
Gary E
GE
Swan
Neal L
NL
Benowitz
Rachel F
RF
Tyndale
David V
DV
Conti
Richard A
RA
Brown
Caryn
C
Lerman
Raymond
R
Niaura
D016642:Bupropion / Q000627:therapeutic use*; D002394:Catechol O-Methyltransferase / Q000235:genetics; D015928:Cognitive Behavioral Therapy / Q000379:methods; D003131:Combined Modality Therapy; D004298:Dopamine / Q000235:genetics*; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics; D018765:Dopamine Uptake Inhibitors / Q000627:therapeutic use*; D004311:Double-Blind Method; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D050638:Receptors, Dopamine D4 / Q000235:genetics; D012907:Smoking / Q000235:genetics; D016540:Smoking Cessation; D000074606:Smoking Prevention; D020080:Tandem Repeat Sequences / Q000235:genetics
C493599:DRD4 protein, human; D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; C493214:SLC6A3 protein, human; D016642:Bupropion; D050638:Receptors, Dopamine D4; C588010:COMT protein, human; D002394:Catechol O-Methyltransferase; C489948:ANKK1 protein, human; D017346:Protein Serine-Threonine Kinases; D004298:Dopamine
Bupropion; first lapse; genetic; pharmacogenetic analysis; randomized clinical trial