Our data show that rs1051730–rs16969968 genotype is strongly associated with tobacco exposure measured objectively via cotinine levels and that this association is robust even after adjustment for self-reported cigarette consumption. We used the per-allele association of genotype on cotinine levels to estimate the association between rs1051730–rs16969968 genotype and lung cancer risk, using published data on the association between cotinine levels and lung cancer risk. Our estimate of the association between genotype and lung cancer risk was consistent with previously reported estimates, even though we were only able to capture point prevalence smoking intensity (ie, based on current smoking only), and not lifetime exposure. These data therefore support the conclusion that association of rs1051730–rs16969968 genotype with lung cancer risk is mediated largely, if not wholly, via tobacco exposure. Although some studies have suggested a direct contribution of rs1051730–rs16969968 genotype to lung carcinogenesis, these have typically relied on self-report measures of smoking behavior which, as we have shown, do not fully capture actual exposure.
