Twin studies provide consistent support for the heritability of nicotine metabolism (Swan et al., 2004, 2005). Accordingly, several functional polymorphisms in the CYP2A6 gene that affect enzyme activity have been characterized (Fernandez-Salguero et al., 1995; Goodz and Tyndale, 2002; Mwenifumbo et al., 2008a) (http://www.imm.ki.se/CYPalleles/cyp2a6.html). To date, the most widely studied polymorphisms are the CYP2A6*2 (L160H amino-acid substitution, lacking activity) (Yamano et al., 1990), CYP2A6*4 (deletion variant lacking activity) (Kitagawa et al., 1999; Nunoya et al., 1998), CYP2A6*9 (48T>G substitution in the TATA promoter region; 50% reduced enzyme activity) (Nakajima et al., 2006), and CYP2A6*12 (10 amino-acid substitution; decreased enzyme activity) (Benowitz et al., 2006b). The *2 and *4 variants are more common in Asian populations than in persons of European ancestry (Malaiyandi et al., 2005; Nakajima et al., 2001). Since all of these reduced activity alleles have relatively low frequency in the general population, genetic subgroups of individuals have been combined in some studies to represent those with variants associated with slow (less that 50% CYP2A6 activity), intermediate (80% CYP2A6 activity), and normal metabolism (100% CYP2A6 activity; Benowitz et al.,
