Of the nicotine metabolism genes, those encoding nicotine-metabolizing enzymes (CYP2A6 and CYP2B6) have been most investigated.104 Six studies have provided consistent evidence that variants leading to reduced or absent CYP2A6 activity are associated with various smoking-related phenotypes, including the nicotine metabolite ratio,105 time to smoking relapse,27 exhaled carbon monoxide (CO),28 initial subjective response to nicotine,82 FTND,13 and CPD.106 All six samples consisted of subjects of European descent (Table 1). The negative result of CYP2A6 in the 2004 meta-analytic review contrasts with the findings from more recent studies, which we believe offer stronger statistical evidence.107 Such significant association of variants in the EGLN2-CYP2A6-CYP2B6 region with ND is corroborated by GWAS results, as discussed in the next section.18, 26
