The Role of Pharmacogenetics in Smoking

Smoking continues to be the leading preventable contributor to death worldwide. Twin studies have suggested a significant genetic contribution underlying most smoking behaviors (40-70% heritability estimates). Candidate gene studies of smoking phenotypes have identified several pharmacogenes implicated in nicotine's pharmacokinetics (CYP2A6, CYP2B6, CYP2A13, FMOs, UGTs, and OCT2), and nicotine's pharmacodynamic response in the central nervous system (nicotinic acetylcholine receptors, as well as through the dopaminergic and serotonergic systems). Subsequent genome-wide association studies (GWAS) have confirmed the role of certain pharmacogenes through hypothesis-free approaches. Furthermore, pharmacogenes that alter the efficacy of smoking cessation pharmacotherapies, including nicotine replacement therapies, bupropion, and varenicline, may also impact quitting success. In this brief review we highlight the role of pharmacogenes in smoking behaviors, such as smoking status, consumption, nicotine dependence, spontaneous quitting, and altered abstinence to pharmacotherapies; We provide examples from initial candidate gene associations and subsequent GWAS. The genes CYP2A6 and the CHRNA5-A3-B4 confer the most replicated sources of genetic variation in smoking behaviors, likely due to their importance in nicotine's pharmacology. We will also provide examples of genetic scoring approaches, and the role of rare variants in explaining a portion of the missing heritability in smoking behaviors.