The 19q13 locus contains several CYP2 genes, including CYP2A6 - the major enzyme involved in the metabolism of nicotine. CYP2A6 catalyzes C-oxidation of nicotine to cotinine, which is in turn metabolized to trans-3′-hydroxycotinine (44,45) It would seem plausible that genetic variants in this gene may induce slower nicotine metabolism(12,46) and accumulation of circulating cotinine, and subsequently, a reduction in smoking intensity with a lower lung cancer risk as consequence. While this hypothesis would explain the opposing effects of 19q13 SNPs on cotinine and CPD, circulating measurements of the ratio of 3′-hydroxycotinine to cotinine would be required to further elucidate these complex associations. Overall, these observations highlight the disparate mechanisms of variants on 15q25 and 19q13 in their effects on smoking behavior and subsequent lung cancer risk. To our knowledge, the present study is the largest to date investigating the effects of SNPs on 7p14, 8p11, 10q23, 15q25, and 19q13, on lung cancer risk, that also utilizes circulating cotinine measures as proxies for recent smoking behavior. The study further benefits from several important characteristics, including the prospective study design and detailed
