Genome-Wide Association of the Laboratory-Based Nicotine Metabolite Ratio in Three Ancestries.
Nicotine Tob Res
; 18(9): 1837-1844, 2016 09.
Article
em En
| MEDLINE
| ID: mdl-27113016
ABSTRACT
INTRODUCTION:
Metabolic enzyme variation and other patient and environmental characteristics influence smoking behaviors, treatment success, and risk of related disease. Population-specific variation in metabolic genes contributes to challenges in developing and optimizing pharmacogenetic interventions. We applied a custom genome-wide genotyping array for addiction research (Smokescreen), to three laboratory-based studies of nicotine metabolism with oral or venous administration of labeled nicotine and cotinine, to model nicotine metabolism in multiple populations. The trans-3'-hydroxycotinine/cotinine ratio, the nicotine metabolite ratio (NMR), was the nicotine metabolism measure analyzed.METHODS:
Three hundred twelve individuals of self-identified European, African, and Asian American ancestry were genotyped and included in ancestry-specific genome-wide association scans (GWAS) and a meta-GWAS analysis of the NMR. We modeled natural-log transformed NMR with covariates principal components of genetic ancestry, age, sex, body mass index, and smoking status.RESULTS:
African and Asian American NMRs were statistically significantly (P values ≤ 5E-5) lower than European American NMRs. Meta-GWAS analysis identified 36 genome-wide significant variants over a 43 kilobase pair region at CYP2A6 with minimum P = 2.46E-18 at rs12459249, proximal to CYP2A6. Additional minima were located in intron 4 (rs56113850, P = 6.61E-18) and in the CYP2A6-CYP2A7 intergenic region (rs34226463, P = 1.45E-12). Most (34/36) genome-wide significant variants suggested reduced CYP2A6 activity; functional mechanisms were identified and tested in knowledge-bases. Conditional analysis resulted in intergenic variants of possible interest (P values < 5E-5).CONCLUSIONS:
This meta-GWAS of the NMR identifies CYP2A6 variants, replicates the top-ranked single nucleotide polymorphism from a recent Finnish meta-GWAS of the NMR, identifies functional mechanisms, and provides pan-continental population biomarkers for nicotine metabolism. IMPLICATIONS This multiple ancestry meta-GWAS of the laboratory study-based NMR provides novel evidence and replication for genome-wide association of CYP2A6 single nucleotide and insertion-deletion polymorphisms. We identify three regions of genome-widesignificance:
proximal, intronic, and distal to CYP2A6. We replicate the top-ranking single nucleotide polymorphism from a recent GWAS of the NMR in Finnish smokers, identify a functional mechanism for this intronic variant from in silico analyses of RNA-seq data that is consistent with CYP2A6 expression measured in postmortem lung and liver, and provide additional support for the intergenic region between CYP2A6 and CYP2A7.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Tabagismo
/
Fumar
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Citocromo P-450 CYP2A6
/
Nicotina
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Adult
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Female
/
Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Nicotine Tob Res
Assunto da revista:
SAUDE PUBLICA
Ano de publicação:
2016
Tipo de documento:
Article
País de afiliação:
Canadá