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

Chenoweth, Meghan J and Ware, Jennifer J and Zhu, Andy Z X and Cole, Christopher B and Cox, Lisa Sanderson and Nollen, Nikki and Ahluwalia, Jasjit S and Benowitz, Neal L and Schnoll, Robert A and Hawk, Larry W and Cinciripini, Paul M and George, Tony P and Lerman, Caryn and Knight, Joanne and Tyndale, Rachel F (2018) Genome-wide association study of a nicotine metabolism biomarker in African American smokers : impact of chromosome 19 genetic influences. Addiction, 113 (3). pp. 509-523. ISSN 0965-2140

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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 ~9.5 kb 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 individuals of European descent. 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.

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This is the peer reviewed version of the following article: Chenoweth, M. J., Ware, J. J., Zhu, A. Z. X., Cole, C. B., Cox, L. S., Nollen, N., Ahluwalia, J. S., Benowitz, N. L., Schnoll, R. A., Hawk, L. W. Jr, Cinciripini, P. M., George, T. P., Lerman, C., Knight, J., Tyndale, R. F., and on behalf of the PGRN-PNAT Research Group (2018) Genome-wide association study of a nicotine metabolism biomarker in African American smokers: impact of chromosome 19 genetic influences. Addiction, 113: 509–523. doi: 10.1111/add.14032 which has been published in final form at This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.
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23 Nov 2017 00:29
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09 Jan 2024 00:20