Genome‐wide association study of a nicotine metabolism biomarker in African American smokers: impact of chromosome 19 genetic influences

Background and aims The activity of CYP2A6, the major nicotine-inactivating enzyme, is measurable in smokers using the nicotine metabolite ratio (NMR; 3’hydroxycotinine/cotinine). Due to its role in nicotine clearance, the NMR is associated with smoking behaviours and response to pharmacotherapies. The NMR is highly heritable (~80%), and on average lower in African Americans (AA) versus Whites. We previously identified several reduce and loss-of-function CYP2A6 variants common in individuals of African descent. Our current aim was to identify novel genetic influences on the NMR in AA smokers using genome-wide approaches. Design Genome-wide association study (GWAS). Setting Multiple sites within Canada and the United States. Participants AA smokers from two clinical trials: Pharmacogenetics of Nicotine Addiction Treatment (PNAT)-2 (NCT01314001; n=504) and Kick-it-at-Swope (KIS)-3 (NCT00666978; n=450). Measurements Genome-wide SNP genotyping, the NMR (phenotype), and population substructure and NMR covariates. Findings Meta-analysis revealed three independent chromosome 19 signals (rs12459249, rs111645190, and rs185430475) associated with the NMR. The top overall hit, rs12459249 (P=1.47e-39; beta=0.59 per C (versus T) allele, SE=0.045), located ~9.5kb 3’ of CYP2A6, remained genome-wide significant after controlling for the common (~10% in AA) non-functional CYP2A6*17 allele. In contrast, rs111645190 and rs185430475 were not genome-wide significant when controlling for CYP2A6*17. In total, 96 signals associated with the NMR were identified; many were not found in prior NMR GWASs in European descent individuals. The top hits were also associated with the NMR in a third cohort of AA (KIS2; n=480). None of the hits were in UGT or OCT2 genes. Conclusions Three independent chromosome 19 signals account for ~20% of the variability in the nicotine metabolite ratio in African-American smokers. The hits identified may contribute to inter-ethnic variability in nicotine metabolism, smoking behaviours, and tobacco-related disease risk.