This study represents the first genetic association study of varenicline for smoking cessation. The pharmacogenetic analysis, focusing largely on gene loci encoding nicotinic cholinergic receptor subunits and drug metabolizing enzymes, offers preliminary evidence that variants in CHRNA4, CHRNB2, and CHRNA7 as well as in the 15q25 LD chromosomal region, including the nAChR genes CHRNA3, CHRNA5, and CHRNB4, influence the outcome (success or failure) of smoking cessation attempts with varenicline. In contrast, genetic analysis of response to bupropion suggests that the success of smoking cessation with this drug is determined in part by variation in CYP2B6, the gene encoding the primary enzyme responsible for the metabolism of bupropion (Faucette et al, 2000), rather than by genetic variation in nicotinic cholinergic receptor pathways. In addition to smoking cessation pharmacogenetics, we also evaluated pharmacogenetic associations with the presence of nausea while attempting to quit smoking, as well as relapse to smoking following a successful period of continuous abstinence. As with response to varenicline, genetic variation in the nicotinic cholinergic receptor genes appears to contribute to the risk of experiencing nausea during smoking cessation, and interestingly, relapse to smoking was significantly associated with polymorphisms in the serotonergic receptor genes, HTR3A and HTR3B.
