Grant: Project Grant

Cigarette smoking is a leading cause of preventable illness and death in Canada; using precision medicine genomics approaches we plan to personalize smoking cessation treatment choices. In this proposal, we seek to identify genetic factors that influence the nicotine metabolite ratio (NMR), a measure of nicotine inactivation that predicts treatment outcomes in multiple smoking cessation clinical trials. NMR is also associated with the amount smoked, dependence, reactivity to smoking cues, risk for lung cancer, and many other smoking-related behaviours; in general, faster nicotine metabolizers (higher NMR) smoke more, are more dependent, have lower quit rates, and a higher risk for lung cancer, compared to slower metabolizers. Up to 80% of NMR variability between smokers is due to genetics, however only a small fraction of this genetic variation is known. While NMR itself could be used clinically to personalize smoking cessation, this is not yet possible because measuring NMR requires sophisticated techniques; there are no commercially available NMR kits and NMR is not routinely measured. In contrast, DNA, from which genetic information can be determined, is more easily collected. Thus, using genetics to better understand NMR, and how NMR is related to smoking and illness, we will enhance quitting and reduce tobacco-related illness and death. Our goal is to sequence (i.e., read) the major nicotine inactivation gene in ~1000 smokers to identify specific variants affecting NMR. We also have data from 9 smoking cessation clinical trials, where >5,000 smokers with NMR will be examined for the variants identified in our sequencing analyses. We will then study how these variants functionally influence NMR, smoking behaviours, and cessation outcomes using this unparalleled clinical resource. Through these analyses, we will improve our ability to genetically tailor treatment, which will ultimately improve smoking cessation rates and the mortality associated with smoking.