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 selfreported 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). CIHR Author Manuscript CIHR Author Manuscript CIHR Author ManuscriptConclusions-Our findings extend previous work indicating that slow nicotine metabolism mediated by CYP2A6, and perhaps CYP2B6, increases risk for tobacco dependence throughout adolescence.

CYP2A6 metabolism in the development of smoking behaviors in young adults

“…O'Loughlin et al (2004) followed 228 nondependent smokers in grade seven over approximately 30 months and found that individuals with less active genetic variants in CYP2A6 were more likely to develop nicotine dependence but smoked fewer cigarettes per day once dependent. In a follow-up study examining 421 adolescents who had ever smoked a cigarette, Chenoweth et al (2016) similarly found that slow metabolism conferred by CYP2A6 variation was associated with increased risk of nicotine dependence in adolescence. Huang et al (2005) examined variation in CYP2A6 in 1518 adolescents enrolled in a longitudinal study in the United Kingdom and similarly found that individuals with variants associated with slower metabolism were more likely to be current versus former smokers at age 18 years compared with normal metabolizers.…”

“…For example, Audrain-McGovern (2007) examined 222 adolescent ever-smokers of European ancestry and found that normal CYP2A6 metabolizers developed symptoms of dependence at a faster rate than slower CYP2A6 metabolizers. Other studies suggest that the increased risk of slower metabolizers for developing nicotine dependence in adolescence disappears by young adulthood (Chenoweth et al, 2016). Cannon et al (2016) followed 296 participants across ages 16-24 years and found that using a CYP2A6 diplotype predictive metric, intermediate metabolism compared with slow and normal was a risk factor for smoking frequency and nicotine dependence.…”

“…Some studies suggest that slow nicotine metabolism is associated with an increased risk of nicotine dependence (Chenoweth et al, 2016; O'Loughlin et al, 2004; Rubinstein et al, 2013), possibly reflecting an increased sensitivity to initial nicotine exposure among youth who metabolize nicotine more slowly. In contrast, other studies suggest that slower metabolizers have a decreased risk for dependence and related symptoms (Audrain-McGovern et al, 2007; Rubinstein et al, 2008), paralleling findings in adults regarding reduced heaviness of smoking among slow metabolizers.…”

“…Studies in youth present conflicting results regarding the effect of nicotine metabolism on the development of nicotine dependence and other smoking behaviors (Audrain-McGovern et al, 2007;Cannon et al, 2016;Chenoweth et al, 2016;Huang et al, 2005;Moolchan et al, 2009;O'Loughlin et al, 2004;Rubinstein et al, 2008;Rubinstein et al, 2013). Some studies suggest that slow nicotine metabolism is associated with an increased risk of nicotine dependence (Chenoweth et al, 2016;O'Loughlin et al, 2004;Rubinstein et al, 2013), possibly reflecting an increased sensitivity to initial nicotine exposure among youth who metabolize nicotine more slowly. In contrast, other studies suggest that slower metabolizers have a decreased risk for dependence and related symptoms (Audrain-McGovern et al, 2007;Rubinstein et al, 2008), paralleling findings in adults regarding reduced heaviness of smoking among slow metabolizers.…”

Nicotine-N′-Oxidation by Flavin Monooxygenase Enzymes

“…Similarly, genetic variants in several UGTs are correlated with differences in the glucuronidation of urinary nicotine, cotinine, and 3-hydroxycotinine (24,25). Genome-wide association studies (GWAS) have identified associations between FMO1 and FMO3 SNPs and nicotine dependence (7,19,(26)(27)(28). Previous studies have shown that genetic variations in FMO3 in different smoker cohorts were associated with nicotine dependence (28), while a recent in vivo study demonstrated an association between the FMO3 E308G/E158K haplotype with nicotine-N 0 -oxidation and smoking behavior (29).…”