and collection of biological sample for cotinine analysis), and the time of day that cotinine samples were collected was not standardized, either within or between samples. However, the relatively long half-life of cotinine means it provides a reasonably stable measure of exposure in regular cigarette smokers. Also, the lack of substantial between-study heterogeneity again suggests that the impact of this was modest. Fourth, we were unable to capture interindividual variation in cotinine metabolism, for example due to genetic variation within cytochrome P450, family 2, subfamily A, polypeptide 6 (CYP2A6), which encodes the CYP2A6 enzyme primarily responsible for the metabolism of nicotine to cotinine (54). Therefore, although cotinine levels provide a considerably more precise measure of tobacco exposure than self-report measures, including measures of CYP2A6 activity might serve to refine this further. It is also possible that increased nicotine consumption among rs1051730–rs16969968 risk allele carriers may result in CYP2A6 enzyme induction, giving rise to a positive feedback cycle as faster metabolism of nicotine leads to increased consumption to maintain circulating levels (55). However, evidence suggests that nicotine metabolism is inhibited in smokers compared with nonsmokers (56). We also did not adjust for other factors known to influence nicotine metabolism, such as
