title: Pharmacotherapy effects on smoking cessation vary with nicotine metabolism gene (CYP2A6).
abstract: OBJECTIVE
  Evidence suggests that both the nicotinic receptor α5 subunit (CHRNA5) and Cytochrome P450 2A6 (CYP2A6) genotypes influence smoking cessation success and response to pharmacotherapy. We examine the effect of CYP2A6 genotype on smoking cessation success and response to cessation pharmacotherapy, and combine these effects with those of CHRNA5 genotypes.
  
  
  METHODS
  Placebo-controlled randomized smoking cessation trial.
  
  
  METHODS
  Ambulatory care facility in Wisconsin, USA.
  
  
  METHODS
  Smokers (n = 709) of European ancestry were randomized to placebo, bupropion, nicotine replacement therapy or combined bupropion and nicotine replacement therapy.
  
  
  METHODS
  Survival analysis was used to model time to relapse using nicotine metabolism derived from CYP2A6 genotype-based estimates. Slow metabolism is defined as the lowest quartile of estimated metabolic function.
  
  
  RESULTS
  CYP2A6-defined nicotine metabolic function moderated the effect of smoking cessation pharmacotherapy on smoking relapse over 90 days [hazard ratio (HR) = 2.81, 95% confidence interval (CI) = 1.32-5.99, P = 0.0075], with pharmacotherapy significantly slowing relapse in fast (HR = 0.39, 95% CI = 0.28-0.55, P = 1.97 × 10(-8)), but not slow metabolizers (HR = 1.09, 95% CI = 0.55-2.17, P = 0.80). Further, only the effect of nicotine replacement, and not bupropion, varies with CYP2A6-defined metabolic function. The effect of nicotine replacement on continuous abstinence is moderated by the combined genetic risks from CYP2A6 and CHRNA5 (Wald = 7.44, d.f. = 1, P = 0.0064).
  
  
  CONCLUSIONS
  Nicotine replacement therapy is effective among individuals with fast, but not slow, CYP2A6-defined nicotine metabolism. The effect of bupropion on relapse likelihood is unlikely to be affected by nicotine metabolism as estimated from CYP2A6 genotype. The variation in treatment responses among smokers with genes may guide future personalized smoking cessation interventions.
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Li-Shiun
authors.initials: LS
authors.lastname: Chen
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: A Joseph
authors.initials: AJ
authors.lastname: Bloom
authors.affiliation: Tobacco Research and Intervention, University of Wisconsin, School of Medicine, Madison, WI53711.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Baker
authors.affiliation: Tobacco Research and Intervention, University of Wisconsin, School of Medicine, Madison, WI53711.
authors.forename: Stevens S
authors.initials: SS
authors.lastname: Smith
authors.affiliation: Tobacco Research and Intervention, University of Wisconsin, School of Medicine, Madison, WI53711.
authors.forename: Megan E
authors.initials: ME
authors.lastname: Piper
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Maribel
authors.initials: M
authors.lastname: Martinez
authors.affiliation: Department of Genetics, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Nancy
authors.initials: N
authors.lastname: Saccone
authors.affiliation: Department of Psychiatry, University of Minnesota, Minneapolis, MN 55455.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hatsukami
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 63110.
authors.forename: Laura
authors.initials: L
authors.lastname: Bierut
mesh_terms: D000328:Adult; D001483:Base Sequence; D016642:Bupropion / Q000627:therapeutic use*; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics*; D018765:Dopamine Uptake Inhibitors / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics; D009538:Nicotine / Q000378:metabolism*; D016016:Proportional Hazards Models; D011978:Receptors, Nicotinic / Q000235:genetics; D012008:Recurrence; D012907:Smoking / Q000188:drug therapy*; D016540:Smoking Cessation / Q000379:methods*; D061485:Tobacco Use Cessation Devices; D016896:Treatment Outcome
chemical_list: C447158:CHRNA5 protein, human; D018765:Dopamine Uptake Inhibitors; D009419:Nerve Tissue Proteins; D011978:Receptors, Nicotinic; D016642:Bupropion; D009538:Nicotine; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6
keywords: Metabolism; nicotine; pharmacogenetics; smoking cessation
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