title: Nicotinic acetylcholine receptor variation and response to smoking cessation therapies.
abstract: OBJECTIVE
  To evaluate the association of nicotinic acetylcholine receptor (nAChR) single nucleotide polymorphism (SNP) with 7-day point prevalence abstinence (abstinence) in randomized clinical trials of smoking cessation therapies in individuals grouped by pharmacotherapy randomization to inform the development of personalized smoking cessation therapy.
  
  
  METHODS
  We quantified association of four SNPs at three nAChRs with abstinence in eight randomized clinical trials. Participants were 2633 outpatient treatment-seeking, self-identified European ancestry individuals smoking at least 10 cigarettes/day, recruited through advertisement, prescribed pharmacotherapy, and provided with behavioral therapy. Interventions included nicotine replacement therapy (NRT), bupropion, varenicline, placebo (PLA), or combined NRT and bupropion, and five modes of group and individual behavioral therapy. Outcome measures tested in multivariate logistic regression were end of treatment and 6 month (6MO) abstinence, with demographic, behavioral, and genetic covariates.
  
  
  RESULTS
  'Risk' alleles previously associated with smoking heaviness were significantly (P<0.05) associated with reduced abstinence in the PLA pharmacotherapy group (PG) at 6MO [for rs588765, odds ratio (95% confidence interval) 0.41 (0.17-0.99)], and at end of treatment and at 6MO [for rs1051730, 0.42 (0.19-0.93) and 0.31 (0.12-0.80)], and with increased abstinence in the NRT PG at 6MO [for rs588765, 2.07 (1.11-3.87) and for rs1051730, 2.54 (1.29-4.99)]. We observed significant heterogeneity in rs1051730 effects (F=2.48, P=0.021) between PGs.
  
  
  CONCLUSIONS
  chr15q25.1 nAChR SNP risk alleles for smoking heaviness significantly increase relapse with PLA treatment and significantly increase abstinence with NRT. These SNP-PG associations require replication in independent samples for validation, and testing in larger sample sizes to evaluate whether similar effects occur in other PGs.
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, CA 94025, USA. andrew.bergen@sri.com
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Bergen
authors.forename: Harold S
authors.initials: HS
authors.lastname: Javitz
authors.forename: Ruth
authors.initials: R
authors.lastname: Krasnow
authors.forename: Denise
authors.initials: D
authors.lastname: Nishita
authors.forename: Martha
authors.initials: M
authors.lastname: Michel
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.forename: Jinghua
authors.initials: J
authors.lastname: Liu
authors.forename: Won
authors.initials: W
authors.lastname: Lee
authors.forename: Christopher K
authors.initials: CK
authors.lastname: Edlund
authors.forename: Sharon
authors.initials: S
authors.lastname: Hall
authors.forename: Pui-Yan
authors.initials: PY
authors.lastname: Kwok
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Baker
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
mesh_terms: D000328:Adult; D018687:Antidepressive Agents, Second-Generation / Q000494:pharmacology; D001521:Behavior Therapy; D001552:Benzazepines / Q000494:pharmacology; D016642:Bupropion / Q000494:pharmacology; D005260:Female; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000494:pharmacology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011810:Quinoxalines / Q000494:pharmacology; D011978:Receptors, Nicotinic / Q000235:genetics*; D012008:Recurrence; D012907:Smoking / Q000235:genetics* / Q000628:therapy; D016540:Smoking Cessation; D000068580:Varenicline
chemical_list: D018687:Antidepressive Agents, Second-Generation; D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; D016642:Bupropion; D009538:Nicotine; D000068580:Varenicline