title: Genetically decreased CYP2A6 and the risk of tobacco dependence: a prospective study of novice smokers.
abstract: OBJECTIVE
  Case control studies in adults suggest that defective alleles in the gene that codes for the hepatic cytochrome P450 2A6 (CYP2A6) protect against nicotine dependence (ND) and higher levels of cigarette consumption. These two hypotheses were tested in young adolescents.
  
  
  METHODS
  Self reports of tobacco use and ND symptoms were collected every 3-4 months in a prospective study of 1293 grade 7 students from a convenience sample of 10 schools.
  
  
  METHODS
  281 smokers with genetic data were analysed; those who were not already tobacco dependent and who had inhaled (n = 228) were followed 29.9 months on average, until they became dependent or were censored.
  
  
  METHODS
  The association between metabolic activity, represented by CYP2A6 genotype, and conversion to dependence was analysed using Cox's proportional hazards model.
  
  
  RESULTS
  During follow up 67 subjects (29.4%) became dependent. Relative to CYP2A6*1/*1, having 1-2 copies of the inactive CYP2A6*2 or *4 variant was a strong risk factor for developing dependence (hazard ratio 2.8, 95% confidence 1.3 to 6.3). Subjects with 1-2 partially inactive CYP2A6*9 or *12 variants were not at increased risk. Mean past-week cigarette consumption at the end of follow up (controlling for age, sex, and number of months since first inhalation) among dependent subjects was 29.1 among normal inactivators, compared to 17.2, and 12.7 among slower (1-2 copies of *9 or *12), and slowest (1-2 copies of *2 or *4) inactivators, respectively (p = 0.09).
  
  
  CONCLUSIONS
  Adolescents with 1-2 copies of CYP2A6*2 or *4 are at substantially increased risk of becoming dependent but smoke less once dependent. Genetic risk for ND may need to be considered in the conceptualisation of tobacco control programmes for adolescents.
authors.affiliation: Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, 1020 Pine Avenue West, Montréal, Québec, Canada H3A 1A3. jennifer.oloughlin@mcgill.ca
authors.forename: J
authors.initials: J
authors.lastname: O'Loughlin
authors.forename: G
authors.initials: G
authors.lastname: Paradis
authors.forename: W
authors.initials: W
authors.lastname: Kim
authors.forename: J
authors.initials: J
authors.lastname: DiFranza
authors.forename: G
authors.initials: G
authors.lastname: Meshefedjian
authors.forename: E
authors.initials: E
authors.lastname: McMillan-Davey
authors.forename: S
authors.initials: S
authors.lastname: Wong
authors.forename: J
authors.initials: J
authors.lastname: Hanley
authors.forename: R F
authors.initials: RF
authors.lastname: Tyndale
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics*; D065637:Cytochrome P-450 CYP2A6; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D006899:Mixed Function Oxygenases / Q000235:genetics*; D010290:Parents; D011446:Prospective Studies; D012307:Risk Factors; D012907:Smoking / Q000235:genetics*; D014029:Tobacco Use Disorder / Q000235:genetics*
chemical_list: D006899:Mixed Function Oxygenases; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6