from the use of sensitive biomarkers of tobacco exposure. Future studies of mechanisms require biomarkers such as cotinine levels. The mechanisms underlying CYP2A6 and smoking cessation is not entirely clear, the complex genetic architecture in this chromosomal region and other metabolic pathways in addition to nicotine metabolism could play a role. Third, the CYP2A6 gene is highly polymorphic (33), including many variants in Europeans (10). Its complex genetic architecture challenges the examination of this gene. We may not have captured other important genetic variation in this region which could have contributed to the results. We used a CYP2A6 genotype-based nicotine metabolism estimate derived from an experiment performed in an independent sample (7, 11). Our findings using a genetic metric of CYP2A6 activity provide a complementary research paradigm, but it is certainly possible that different results would have been obtained through use of the NMR. Finally, given such limitations, further work is clearly needed to develop a treatment algorithm that enhances the effectiveness and cost-effectiveness of smoking treatment.
