dominance of one enzyme, CYP2A6, over nicotine’s conversion to cotinine. However, after correcting for CYP2A6 genotype, D2-cotinine: (D2-nicotine + D2-cotinine) is normally distributed for common diplotypes (Supplemental Table 2 and Supplemental Fig.2), indicating that the skew in this metric results from the allelic frequencies of the ‘gene of large effect’. In addition, because the ratio D2-cotinine: (D2-nicotine + D2-cotinine) ranges between 0 and 1 it has the advantage that it can be easily used to model possible non-additive effects of genotype (see below and methods). The ratio of 3′-trans-hydroxycotinine: cotinine is another validated probe of CYP2A6 activity and nicotine clearance, following oral nicotine administration [14]or during ad libitum smoking[13]. The distribution of D2-3′-trans-hydroxycotinine: D2-cotinine is skewed similarly to the distribution of D2-cotinine: D2-nicotine (Supplemental Fig.3). All three metrics are summarized in Table 3 for comparison in all diplotypes that occur in two or more subjects.
