title: Variation in CYP2A6 and tobacco dependence throughout adolescence and in young adult smokers.
abstract: BACKGROUND
  Smoking is influenced by genetic factors including variation in CYP2A6 and CYP2B6, which encode nicotine-metabolizing enzymes. In early adolescence, CYP2A6 slow nicotine metabolism was associated with higher dependence acquisition, but reduced cigarette consumption. Here we extend this work by examining associations of CYP2A6 and CYP2B6 with tobacco dependence acquisition in a larger sample of smokers followed throughout adolescence.
  
  
  METHODS
  White participants from the Nicotine Dependence in Teens cohort that had ever inhaled (n=421) were followed frequently from age 12-18 years. Cox's proportional hazards models compared the risk of ICD-10 tobacco dependence acquisition (score 3+) for CYP2A6 and CYP2B6 metabolism groups. Early smoking experiences, as well as amount smoked at end of follow-up, was also computed. At age 24 (N=162), we assessed concordance between self-reported cigarette consumption and salivary cotinine.
  
  
  RESULTS
  In those who initiated inhalation during follow-up, CYP2A6 slow (vs. normal) metabolizers were at greater risk of dependence (hazards ratio (HR)=2.3; 95% CI=1.1, 4.8); CYP2B6 slow (vs. normal) metabolizers had non-significantly greater risk (HR=1.5; 95% CI=0.8, 2.6). Variation in CYP2A6 or CYP2B6 was not significantly associated with early smoking symptoms or cigarette consumption at end of follow-up. At age 24, neither gene was significantly associated with dependence status. Self-reported consumption was associated with salivary cotinine, a biomarker of tobacco exposure, acquired at age 24 (B=0.37; P<0.001).
  
  
  CONCLUSIONS
  Our findings extend previous work indicating that slow nicotine metabolism mediated by CYP2A6, and perhaps CYP2B6, increases risk for tobacco dependence throughout adolescence.
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. Electronic address: meghan.chenoweth@utoronto.ca.
authors.forename: Meghan J
authors.initials: MJ
authors.lastname: Chenoweth
authors.affiliation: Axe Risques à la santé, CRCHUM, Montréal, QC, Canada; Department of Social and Preventive Medicine, School of Public Health, University of Montréal, Montréal, QC, Canada. Electronic address: marie-pierre.sylvestre@umontreal.ca.
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Sylvestre
authors.affiliation: Axe Risques à la santé, CRCHUM, Montréal, QC, Canada; Department of Social and Preventive Medicine, School of Public Health, University of Montréal, Montréal, QC, Canada. Electronic address: gisele.contreras@umontreal.ca.
authors.forename: Gisele
authors.initials: G
authors.lastname: Contreras
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada. Electronic address: m.novalen@utoronto.ca.
authors.forename: Maria
authors.initials: M
authors.lastname: Novalen
authors.affiliation: Axe Risques à la santé, CRCHUM, Montréal, QC, Canada; Department of Social and Preventive Medicine, School of Public Health, University of Montréal, Montréal, QC, Canada. Electronic address: jennifer.oloughlin@umontreal.ca.
authors.forename: Jennifer
authors.initials: J
authors.lastname: O'Loughlin
authors.affiliation: Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), University of Toronto, Toronto, ON, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON, Canada; Department of Psychiatry, University of Toronto, Toronto, ON, Canada. Electronic address: r.tyndale@utoronto.ca.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D000293:Adolescent; D000294:Adolescent Behavior; D000328:Adult; D002648:Child; D015331:Cohort Studies; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D014644:Genetic Variation / Q000235:genetics*; D006801:Humans; D008297:Male; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000175:diagnosis* / Q000453:epidemiology / Q000235:genetics*; D055815:Young Adult
chemical_list: C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6
keywords: Addiction; Adolescent; CYP2A6; CYP2B6; Genetics; Nicotine; Smoking