Key goals of genetic studies of smoking behaviors are to identify the genes that confer a vulnerability to nicotine dependence and that guide the development of effective, ‘personalized’ treatment strategies for smoking cessation. We recently demonstrated that pharmacologic treatment affects cessation differently depending on genotype of the nicotinic receptor subunit gene, CHRNA5 (1), a locus strongly associated with nicotine dependence (2-5); a similar association between this locus and cessation has been reported recently (6). Variation in nicotine metabolism efficiency, and variation in the gene that encodes the primary nicotine metabolism enzyme, cytochrome P450 2A6 (CYP2A6), are also robustly associated with smoking phenotypes, especially cigarette consumption (5, 7-9). CYP2A6 is highly polymorphic, with reduced function alleles producing significantly slower rates of nicotine metabolism. Relatively common variants define multiple CYP2A6 haplotypes in European populations (10), and the large majority of inter-individual variation in metabolism of nicotine to cotinine can be explained by seven polymorphisms among European Americans (11). Several studies have reported an influence of nicotine metabolic rate upon cessation (12-14), although the relation between metabolism and different treatment regimens remains unclear.
