Genome-wide association study of a nicotine metabolism biomarker in African American smokers: impact of chromosome 19 genetic influences.
Addiction
; 113(3): 509-523, 2018 03.
Article
em En
| MEDLINE
| ID: mdl-28921760
ABSTRACT
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Cromossomos Humanos Par 19
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Fumar
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Estudo de Associação Genômica Ampla
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Citocromo P-450 CYP2A6
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Nicotina
Tipo de estudo:
Observational_studies
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Prognostic_studies
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Risk_factors_studies
Limite:
Adult
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Aged
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Aged80
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Female
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Humans
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Male
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Middle aged
País/Região como assunto:
America do norte
Idioma:
En
Revista:
Addiction
Assunto da revista:
TRANSTORNOS RELACIONADOS COM SUBSTANCIAS
Ano de publicação:
2018
Tipo de documento:
Article
País de afiliação:
Canadá