To date, the most widely studied CYP2A6 variants include CYP2A6*2 (rs1801272, L160H) which encodes a catalytically inactive enzyme, a whole gene deletion allele CYP2A6*4, CYP2A6*9 (rs28399433, -48T>G), which has an alteration in the TATA box resulting in lower expression of a structurally normal protein, and CYP2A6*12 discussed above [13]. Of these characterized reduced-activity variants, our data included CYP2A6*2 and CYP2A6*9, both of which showed genome-wide significant association but were not identified as independent signals in conditional analyses. A previous very large (N = 85997) meta-analysis of self-reported CPD showed genome-wide significant association on 19q13.2, with strongest evidence obtained for rs4105144, which is in LD with CYP2A6*2 (D′ = 1.0 in CEU) [14]. Similarly, LD between our novel independent signals and both CYP2A6*2 and CYP2A6*9 was high (D’ = 0.89–1.00). The percentage of variance in NMR explained by CYP2A6*2 and CYP2A6*9 in our study cohorts was up to 6% and 12%, respectively. A previous study using an ethnically diverse sample suggested that 15–20% of variance in NMR is accounted for by the four characterized reduced-activity variants (CYP2A6*2, CYP2A6*4, CYP2A6*9, and CYP2A6*12)
