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) [16]; much of the genetic variation would not have been tested for in this study (i.e. CYP2A6*10 –*35). Interestingly, in our study CYP2A6*9 alone explained a large fraction of variance in NMR, possibly due to the higher minor allele frequency in the Finnish cohorts (MAF 0.12–0.14) compared to that reported in the Caucasian population (MAFEUR = 0.07). In addition to CYP2A6*2 and CYP2A6*9, our data set included three additional known alleles, CYP2A6*14 (rs28399435; S29N), CYP2A6*18 (rs1809810; Y392F), and CYP2A6*21 (rs6413474; K476R). Although they are non-synonymous variants, their effect on nicotine clearance likely is minimal. CYP2A6*14 does not appear to affect enzyme activity [57, 58], and although CYP2A6*18 has a decreased activity towards another substrate, coumarin, activity towards nicotine is unaffected [59]. Based on in vivo studies, CYP2A6*21 showed normal activity in a Caucasian population [60]. After conditioning on our top-SNP (rs56113850), none of the five known alleles were genome-wide significant, suggesting that rs56113850 captures information on all of these alleles.
