In addition to genetic variants in the nicotinic receptors contributing to the development of nicotine dependence, genetic variation in nicotine metabolism plays an important role in cigarette consumption (Schoedel et al., 2004; Minematsu et al., 2006) and nicotine dependence (Audrain-McGovern et al., 2007). Conversion of nicotine to cotinine accounts for 70% of initial nicotine metabolism and is performed by the CYP2a6 enzyme (Yamazaki et al., 1999; Su et al., 2000; Malaiyandi et al., 2006). Important functional polymorphisms of CYP2a6 include large deletions and gene recombinations that involve neighboring genes (Oscarson et al., 1999, 2002). The importance of nicotine metabolism and variation in the CYP2a6 region on chromosome 19 was recently reinforced by the GWAS meta-analysis studies in which variants in this region were associated with number of cigarettes smoked per day (Thorgeirsson et al., 2010; Tobacco and Genetics Consortium, 2010). The most significant SNP reported in this region, the intergenic variant rs41405144, lies within two large deletions (defined as CYP2a6*4 and CYP2a6*12). This variant, rs41405144, is correlated with rs1801272, a non-synonymous SNP that defines the CYP2a6*2 loss of function allele.
