The contribution of common CYP2A6 alleles to variation in nicotine metabolism among European–Americans

Abstract

Cytochrome P450 2A6 (CYP2A6) is the primary catalyst of nicotine metabolism. To develop a predictive genetic model of nicotine metabolism, the conversion of deuterated (D2)-nicotine to D2-cotinine was quantified in 189 European Americans and the contribution of CYP2A6 genotype to variability in first-pass nicotine metabolism was assessed. Specifically, 1) single time-point measures of D2-cotinine/(D2-cotinine + D2-nicotine) following oral administration were used as a metric of CYP2A6 activity; 2) the impact of CYP2A6 haplotype was treated as acting multiplicatively; 3) parameter estimates were calculated for all haplotypes in the subject pool, defined by a set of polymorphisms previously reported to affect function, including gene copy number; and 4) a minimum number of predictive polymorphisms are justified to be included in the model based on statistical evidence of differences between haplotypes. The final model includes seven polymorphisms and fits the phenotype, 30 minutes following D2-nicotine oral administration, with R2=0.719. The predictive power of the model is robust: parameter estimates calculated in men (n=89) predict the phenotype in women (n=100) with R2=0.758 and vice versa with R2=0.617; estimates calculated in current smokers (n=102) predict phenotype in former smokers (n=86) with R2=0.690 and vice versa with R2=0.703. Comparisons of haplotypes also demonstrate that CYP2A6*12 is a loss of function allele indistinguishable from CYP2A6*4 and CYP2A6*2 and that the CYP2A6*1B 5′ UTR conversion has negligible impact on metabolism. After controlling for CYP2A6 genotype modest associations were found between increased metabolism and both female gender (p= 4.8×10−4) and current smoking (p=0.02).

A Genome-Wide Association Study In COPD Identifies A Susceptibility Locus On Chromosome 19q13

“…synonymous SNP in CYP2A6 in our COPD cohorts (26), CYPA26 activity is affected by a number of other demonstrated functional variants-both common and rare (40)(41)(42)(43). While we failed to demonstrate an association with cigarette smoking behavior and rs7937 within our case or control groups, both the 15q25 and 19q13 loci have been associated with cotinine levels in other studies that did not find an association with cigarettes per day (44,45), suggesting that standard measures of smoking behavior are incomplete.…”

Beyond Cigarettes Per Day. A Genome-Wide Association Study of the Biomarker Carbon Monoxide

“…Because the CYP2A6 locus is heterogeneous and no single variant can act as a proxy for CYP2A6 activity, we performed additional genotyping and used a predictive model of CYP2A6 activity that provides a continuous estimate of nicotine metabolism based on CYP2A6 genotype (30,31). This estimate is based on six SNPs: rs28399433 (TATA box *9), rs1137115 (V17V), rs28399435 (S29N *14), rs1801272 (L160H *2), rs28399442 (correlated with *12), rs148166815 (Y351H *38), and variation in CYP2A6 gene copy number.…”

CYP2A6Longitudinal Effects in Young Smokers

“…Estimated nicotine metabolic rate was derived from a predicted metabolism metric based on CYP2A6 genotype 17,18 (cf., Supplementary methods, Table S . In this partitioning of the metric, the null CYP2A6 alleles *2 and *4, the likely null allele *12, 18 as well as the homozygous *9/*9 diplotype were assigned to Slow CDPR.…”

“…We sought to characterize the relative effects of normal, intermediate, and slow metabolism alleles over time using growth-curve models with data from eight longitudinal assessments during a 6-year period (from approximately age [16][17][18][19][20][21][22]. Growth-curve models are informative for the question under consideration in that they provide estimates of initial CYP2A6 effects and the rate of phenotypic change associated with CYP2A6 variants over time.…”