The observation that decreased predicted nicotine metabolism is associated with increased risk of nicotine dependence in young adult daily smokers also builds on previous studies conducted in adolescents (step 2 in Figure 3). O’Loughlin et al. (2004) followed 228 non-dependent smokers in grade 7 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 1,518 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 compared to normal metabolizers. Rubinstein et al. (2013) assessed a biomarker of the rate of nicotine metabolism (the nicotine metabolite ratio) in 164 adolescent smokers and found
