A member of the cytochrome P450 family, CYP2A6, is the main metabolic enzyme for nicotine accounting for up to 80% of nicotine clearance [9]. A large number of distinct CYP2A6 (ENSG00000255974) alleles have been identified, including SNPs, duplications, deletions, and conversions (www.cypalleles.ki.se/cyp2a6.htm). CYP2A6 variations have been phenotypically grouped as slow (<50% of activity), intermediate (80% of activity), and normal (100% of activity) metabolizers. Another member of the cytochrome P450 family, CYP2B6, has an approximately 10% catalytic efficiency of the CYP2A6 enzyme in vitro in nicotine c-oxidation, and may play a minor role in nicotine clearance at higher nicotine levels [10] or in the absence of functional CYP2A6. While CYP2A6 is expressed primarily in the liver, CYP2B6 (ENSG00000197408) is expressed at higher levels in the brain, where it may influence localized metabolism of nicotine [11, 12]. Cytochrome P450 drug metabolizing enzymes are rarely highlighted in genome-wide association studies (GWAS) as the allele frequencies of the functional variants are low in most populations [13]. However, in 2010 a very large GWAS meta-analysis of smoking quantity revealed associations of CYP2A6 and CYP2B6 with SNPs that are in strong linkage disequilibrium (LD) with known functional variants [14].
