Chunk #27 — Results — The majority of phenotypic variability following oral nicotine administration is accounted for by identified CYP2A6 polymorphisms
To determine the contributions of different CYP2A6 alleles, as well as gender and current smoking status, to variability in nicotine metabolism, linear regressions were performed to estimate the impact of different haplotypes upon both log (D2-cotinine: D2-nicotine) and D2-cotinine: (D2-nicotine + D2-cotinine) assuming an additive effect of haplotype. In addition, linear regression was performed with D2-cotinine: (D2-nicotine + D2-cotinine) treating the impact of haplotype as multiplicative. Because this metric ranges between 0 and 1 a multiplicative effect of haplotype can be easily be modeled according to the equation 1 – Phenotype = haplotype1 • haplotype2 (see methods). Non-additive effects of genotype upon metabolic ratios are well known [36] and also reflected in the distribution of the data described here (Fig. 3), i.e. the average difference in nicotine metabolism between null/normal heterozygotes and normal homozygotes is notably less than the difference between null homozygotes and null/normal heterozygotes. The multiplicative model attempts to account for this discrepancy by determining parameter estimate for each haplotype in the context of full diplotypes (see methods).
