TY - JOUR

T1 - Genome-wide association study of a nicotine metabolism biomarker in African American smokers

T2 - impact of chromosome 19 genetic influences

AU - Chenoweth, Meghan J

AU - Ware, Jennifer J

AU - Zhu, Andy Z X

AU - Cole, Christopher B

AU - Cox, Lisa Sanderson

AU - Nollen, Nikki

AU - Ahluwalia, Jasjit S

AU - Benowitz, Neal L

AU - Schnoll, Robert A

AU - Hawk, Larry W

AU - Cinciripini, Paul M

AU - George, Tony P

AU - Lerman, Caryn

AU - Knight, Joanne

AU - Tyndale, Rachel F

AU - PGRN-PNAT Research Group

N1 - 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 http://onlinelibrary.wiley.com/doi/10.1111/add.14032/abstract This article may be used for non-commercial purposes in accordance With Wiley Terms and Conditions for self-archiving.

PY - 2018/3

Y1 - 2018/3

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1111/add.14032

DO - 10.1111/add.14032

M3 - Journal article

C2 - 28921760

VL - 113

SP - 509

EP - 523

JO - Addiction

JF - Addiction

SN - 0965-2140

IS - 3

ER -