Nicotine is the primary addictive agent in tobacco and CYP2A6 is the primary catalyst of nicotine metabolism. Smokers with reduced CYP2A6-catalyzed nicotine metabolism smoke fewer cigarettes and smoke each less intensely, thereby lowering their dose of tobacco smoke carcinogens. These researchers have demonstrated an association of CYP2A6 activity with the risk of lung cancer in smokers. However, the risk of lung cancer varies across racial/ethnic group, as does the contribution of CYP2A6 activity to that risk. The relative lung cancer risk of Native Hawaiians is twice that of Whites and the risk of Japanese is half that of Whites at similar smoking levels. Accurate genetic characterization of CYP2A6 variants across racial/ethnic groups will help to define the relative importance of specific variants to nicotine metabolism in each group.
The majority of lung cancer cases occur in former smokers, who remain at an elevated disease risk for up to 25 years after quitting. The challenge is to identify those who are at the greatest risk, and to investigate how individual differences in nicotine metabolism effect that risk. Quantifying nicotine metabolism in ex-smokers is not possible. The goal of this project is to carry out long-range sequencing of CYP2A6 on samples from different racial/ethnic groups, to identify CYP2A6 haplotypes and their relationship to nicotine metabolism in these smokers. The long-term goal is to develop a genetic score to predict CYP2A6-catalyzed nicotine metabolism and to determine the association of that score with the lung cancer risk of ever smokers in a multiethnic cohort.
Research by this group was featured on the MSI website in July 2022: Lung Cancer in Different Ethnic Groups.