Dataset Information

Nicotine metabolite ratio: Comparison of the three urinary versions to the plasma version and nicotine clearance in three clinical studies.

ABSTRACT:

Background

Variation in CYP2A6 activity influences tobacco smoking behaviors and smoking-related health outcomes. Plasma Nicotine Metabolite Ratio (NMR) is a robust phenotypic biomarker of CYP2A6 activity and nicotine clearance. In urine, the NMR has been calculated as a ratio of free trans-3'-hydroxycotinine to free cotinine (NMR_F/F), total trans-3'-hydroxycotinine to free cotinine (NMR_T/F), or total trans-3'-hydroxycotinine to total cotinine (NMR_T/T). We evaluated these three urinary NMR versions relative to plasma NMR and nicotine clearance and elucidated mechanisms of discrepancies among them.

Methods

Baseline plasma and urine biomarker data were available from two smoking cessation clinical trials and one nicotine pharmacokinetic study (total N = 768). NMRs were compared using Pearson correlations, linear regressions and ANOVA analyses. UGT2B10 and UGT2B17 were genotyped.

Results

Urinary NMR_T/F was the most highly related to plasma NMR (R² = 0.70, P <2.2e-16) followed by NMR_F/F (R² = 0.68, P <2.2e-16), while NMR_T/T was less strongly related (R² = 0.60, P <2.2e-16); consistent across study, ethnicity, sex, heaviness of smoking, and analyte analysis. Controlling for cotinine glucuronidation, as a phenotype or UGT2B10 genotype, corrected the NMR_T/T discordance with plasma NMR (P_anova<0.001). Similar findings were obtained for relationships of nicotine clearance with plasma NMR > urinary NMR_T/F > NMR_F/F > NMR_T/T (R² = 0.41 > 0.37 > 0.35 > 0.25 respectively).

Conclusion

Urinary NMR_T/F followed by NMR_F/F are the best urinary alternatives to plasma NMR or nicotine clearance. NMR_T/T has the least utility as it is influenced substantially by variation in cotinine glucuronidation.

Impact

This work highlighted the variation in urinary NMRs, and identified mechanisms for disparities among them, which facilitates their use in predicting smoking-related outcomes.

SUBMITTER: Giratallah HK

PROVIDER: S-EPMC8133391 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Nicotine metabolite ratio: Comparison of the three urinary versions to the plasma version and nicotine clearance in three clinical studies.

Giratallah Haidy K HK Chenoweth Meghan J MJ Addo Newton N Ahluwalia Jasjit S JS Cox Lisa Sanderson LS Lerman Caryn C George Tony P TP Benowitz Neal L NL Tyndale Rachel F RF

Drug and alcohol dependence 20210420

<h4>Background</h4>Variation in CYP2A6 activity influences tobacco smoking behaviors and smoking-related health outcomes. Plasma Nicotine Metabolite Ratio (NMR) is a robust phenotypic biomarker of CYP2A6 activity and nicotine clearance. In urine, the NMR has been calculated as a ratio of free trans-3'-hydroxycotinine to free cotinine (NMR<sub>F/F</sub>), total trans-3'-hydroxycotinine to free cotinine (NMR<sub>T/F</sub>), or total trans-3'-hydroxycotinine to total cotinine (NMR<sub>T/T</sub>). W ...[more]

PMID: 33873029

Similar Datasets

Project description:IntroductionMetabolic 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.MethodsThree 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.ResultsAfrican 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).ConclusionsThis 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.ImplicationsThis 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-wide significance: 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.

Dataset Information

Nicotine metabolite ratio: Comparison of the three urinary versions to the plasma version and nicotine clearance in three clinical studies.

Background

Methods

Results

Conclusion

Impact

Publications

Nicotine metabolite ratio: Comparison of the three urinary versions to the plasma version and nicotine clearance in three clinical studies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets