Genetic variability in CYP2A6 has been associated with a variety of smoking behavior phenotypes. Reduced or null activity CYP2A6 alleles (CYP2A6*9, CYP2A6*12, CYP2A6*2, or CYP2A6*4) are more prevalent in non-smokers than smokers (Iwahashi et al. 2004; Malaiyandi et al. 2005; Mwenifumbo and Tyndale 2007; Pianezza et al. 1998). Smokers with reduced or null activity smoke fewer cigarettes (Audrain-McGovern et al. 2007; Fujieda et al. 2004; Malaiyandi et al. 2005, 2006; Minematsu et al. 2003; Mwenifumbo et al. 2007; Rao et al. 2000; Schoedel et al. 2004; Tyndale et al. 1999) and tend to be less dependent on nicotine (Kubota et al. 2006; Malaiyandi et al. 2006) than smokers with normal activity alleles. With respect to smoking initiation, adolescents with normal activity alleles may progress to nicotine dependence more quickly than slower metabolizers (CYP2A6*9, CYP2A6*12, CYP2A6*2, or CYP2A6*4) (Audrain-McGovern et al. 2007). A recent GWAS conducted in 31,266 smokers found an association of the rs4105144 SNP with reduced smoking quantity, assessed as cigarettes per day (Thorgeirsson et al. 2010). The rs4105144 SNP is in linkage disequilibrium with the CYP2A6*2 reduced activity allele.
