Variation in Smoking and Nicotine Metabolism Among American Indians: Novel Influences on In Vivo and In Vitro Nicotine Metabolism Phenotypes

Tobacco use and associated disease risk vary widely among different populations and ethnic/racial groups. While American Indian and Alaska Native populations collectively have the highest prevalence of smoking, recent studies have highlighted disparities in smoking and disease risk across different American Indian/Alaska Native populations. The Northern Plains American Indian tribal populations of South Dakota have a much higher smoking prevalence, smoke more cigarettes per day, and have higher lung cancer risk than the Southwest American Indian tribe of Arizona. Underlying reasons behind the differences in smoking and lung cancer risk between these tribes remain unknown. We sought to biochemically characterize the level of tobacco exposure among smokers and non-smokers in the Northern Plains and Southwest tribes, using cotinine as a biomarker. We demonstrated that despite both tribes being relatively light smoking populations, secondhand tobacco smoke exposure is high among non-smokers, highlighting a potential source of increased risk for tobacco-related disease. As variation in the rate of nicotine metabolism (i.e. CYP2A6 activity) has been associated with differences in smoking behaviours and lung cancer risk in other ethnic/racial groups, we then evaluated variation in the CYP2A6 gene and the rate of nicotine metabolism in the Northern Plains and Southwest tribes. We identified distinct patterns of CYP2A6 genetic variation across the two tribes, and an overall faster rate of nicotine metabolism in the Northern Plains compared to the Southwest tribe. We then used a human liver bank to explore additional sources (both genetic and non-genetic) of variation in CYP2A6 activity. We identified several independent and shared sources of variation that could translate to variable hepatic clearance of nicotine, and may impact smoking behaviour. Lastly, we searched for CYP2A6 gain of function genetic variants in order to identify sources of faster CYP2A6 activity. Through investigation of novel uncharacterized variation at the CYP2A6 locus using next-generation sequencing, we identified seven novel high frequency CYP2A6 genetic variants and a five-SNP diplotype, which were associated with faster CYP2A6 activity in vitro and in vivo. Overall, our findings provide insight into the patterns of tobacco exposure, CYP2A6 genetic variation, and nicotine metabolism rate in American Indian tribal communities, and expand on our knowledge of genetic and non-genetic sources of variation in nicotine metabolism rate. These findings could improve our understanding of lung cancer risk in these American Indian populations, and help to inform future tobacco cessation efforts.Ph.D.2018-12-19 00:00:0