Introduction
Approximately 90% of smokers begin smoking in adolescence. A substantial proportion (∼40–75%) of smoking behaviour is influenced by genetics. CYP2A6 inactivates nicotine, the principle psychoactive compound in cigarette smoke, to cotinine. Genetic variation in CYP2A6 that reduces the rate of nicotine metabolism is associated with lower cigarette consumption, dependence scores, brain response to smoking cues, and greater cessation, even in adolescence. In adolescents, CYP2A6 slow nicotine metabolism was also associated with an increased risk of tobacco dependence acquisition at young ages (from age12 to 16 years), but slower escalation in nicotine dependence and reduced cigarette consumption. In young adults, CYP2A6 slow (vs. normal) metabolizers were less likely to be smokers. Together these findings suggest that while CYP2A6 slow metabolism increases the risk of becoming a smoker in younger adolescence, slow metabolism also increases cessation, and reduces cigarette consumption independent smokers. However, it is not known whether CYP2A6slow metabolism increases smoking acquisition in later adolescence, a period during which a substantial amount of smoking uptake occurs.
A small proportion (∼10%) of nicotine’s metabolism to cotinine occurs via a second enzyme, CYP2B6. The CYP2B6*6 allele, a prevalent haplotype (∼25% frequency in Whites) is associated with lower CYP2B6 hepatic protein and slower CYP2B6-mediated metabolism of bupropion and efavirenz. In adult smokers, CYP2B6*6 was associated with lower abstinence rates in the placebo arm of a bupropion smoking cessation clinical trial; 15% of individuals with one or two copies of CYP2B6*6 achieved abstinence, compared to 32% of CYP2B6*1/*1 individuals. In a separate study, the CYP2B6*6 allele was more frequent in nicotine dependent individuals compared to those that were not dependent (32%vs. 22%, respectively). Whether CYP2B6*6 also influences the risk for acquiring nicotine dependence in adolescence is not known.
Here we examined associations for CYP2A6 and CYP2B6 with tobacco dependence acquisition in a larger (n > 400) sample of adolescent smokers assessed four times each year across the entire adolescent period (age 12–18 years). We hypothesized that CYP2A6slow (vs. CYP2A6 normal), and that CYP2B6 slow (i.e., individuals with one or two copies of CYP2B6*6) (vs. CYP2B6 normal) metabolizers would be at increased risk of acquiring dependence. We also hypothesized that a larger proportion of slow (vs. normal) metabolizers for each gene would report early smoking experiences, which are associated with the development of nicotine dependence. We also assessed cigarette consumption at the end of follow-up among dependent smokers, hypothesizing that CYP2A6 slow (vs. CYP2A6 normal) metabolizers would smoke fewer cigarettes; no association was expected between CYP2B6genotype groups. For both CYP2A6 and CYP2B6, we further hypothesized that slow (vs. normal) metabolizers would be more likely to be dependent at end of follow-up. At age 24, we expected CYP2A6 slow (vs. normal) metabolizers to be at lower risk of dependence, as CYP2A6 slow metabolizers are less likely to be dependent smokers (vs. non-smokers) as adults. Finally, we hypothesized that CYP2B6 slow (vs. normal) metabolizers would be more likely to be dependent at age 24, consistent with the higher frequency of CYP2B6*6 in dependent (vs. non-dependent) adults.
Finally, an adjunct biochemical analysis to assess the validity of the self-reported cigarette consumption data was undertaken. We examined the construct-related validity of self-reported cigarette consumption against salivary cotinine, widely used as an objective biomarker of tobacco consumption, and also assessed its relationships with nicotine dependence and withdrawal scores.