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Author Notes:

Correspondence: andrew.bergen@sri.com

Contributions: Conceived and designed the experiments: AWB MM HSJ GES.

Performed the experiments: MM RK DN HSJ.

Analyzed the data: AWB MM DN RK HSJ KNC.

Contributed reagents/materials/analysis tools: HSJ DN RK KNC CNL-S HH JBM SMH TBB DVC NLB CL RFT GES TRICL.

Wrote the paper: AWB MM DN RK HSJ KNC CNL-S AZXZ JWB JBM SMH TBB NLB CL RFT GES.

Acknowledgements: We thank: the laboratory study and clinical trial participants for their contributions to research; Eric J. Stanek, Jay Kaufman and Richard Hockett for their contributions to Stage I genotyping; Kirsten Copren and Kathryn Thompson at the University of California San Francisco Helen Diller Family Comprehensive Cancer Center Genome Core for their contributions to Stage II genotyping; Gregory Kronmal, Pius Brzoska, and Elizabeth Pitts of ThermoFisher for their custom TaqMan SNP Genotype assay designs; and Heike Bickeböller of the University of Göttingen, Richard Houlston of the Institute of Cancer Research, Maria Teresa Landi and Neil Caporaso of the National Cancer Institute, Rayjean Hung of the Lunenfeld-Tanenbaum Research Institute, and William Wheeler of Information Management Services for TRICL meta-GWAS database results.

Disclosures: AWB, MM, RK, DN and HSJ had full access to all of the laboratory study and clinical trial data in the study and take responsibility for the integrity and the accuracy of the data analysis of the laboratory study and clinical trial data.

The TRICL Research Team takes responsibility for the integrity and the accuracy of the data analysis of the lung cancer meta-GWAS.

The content of this ms is solely the responsibility of the authors and does not represent the official views of Affymetrix, GlaxoSmithKline, Medco Health Solutions, the National Cancer Institute, the National Institute of Drug Abuse, Pfizer, SRI International, ThermoFisher or the University of California Tobacco Related Disease Research Program.

Medco Health Solutions, Inc. and Affymetrix, Inc. participated with SRI International in the selection of the two clinical laboratory metabolic studies, of the metabolic outcome, and of the DMET Plus Array for genotyping and Affymetrix performed the DMET Plus Array genotyping of the two clinical laboratory metabolic study DNA samples.

No other funders or sponsors had any other role in the design of the laboratory studies, the randomized controlled trials or of this two-stage study, the collection, analysis, or interpretation of data, the writing of, or the decision to submit the ms.

BioRealm, LLC provided support in the form of a salary for author JWB, but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

The specific roles of the authors are articulated in the ‘author contributions’ section.

Competing Interests: AWB reports employment at SRI International.

This project was partly funded by Medco Health Solutions, Inc. (acquired by Express Scripts in 2012) and Affymetrix, Inc.

JWB is an employee and a LLC member of BioRealm.

Varenicline and nominal support for recruiting clinical trial 00301145 participants was provided by Pfizer.

GlaxoSmithKline provided medication for clinical trials 01621022 and 00332644.

GES reports serving as a Pfizer consultant for a one-day meeting in 2008.

SMH has served as a consultant to Gilead, Inc., and Sleepio, Inc.

TBB reports no competing interests in the last five years.

He discloses that in the five years prior to the trials included in this analysis and that he conducted (NCT IDs 01621009, 01621022 and 00332644), he served as a PI or Co-PI on research sponsored by pharmaceutical companies, including GlaxoSmithKline and Pfizer.

He also discloses that he is an author and collaborator on work done by Washington University School of Medicine colleagues LS Chen, AJ Bloom, & LJ Bierut on work examining associations of CYP2A6 with cessation.

NLB reports consultation with pharmaceutical companies that market smoking cessation medications and service as a paid expert witness in ligation against tobacco companies.

CL reports having received research funding from Pfizer.

RFT has consulted with pharmaceutical companies, mostly on smoking cessation.

This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials.

Subjects:

Research Funding:

This work was supported, in part, by: a Research Agreement between Medco Health Solutions, Inc., Affymetrix, Inc., and SRI International; grants and a contract from the National Institute of Drug Abuse, and grants from the National Cancer Institute, of the United States Department of Health and Human Services [R21 DA33813 to AWB; NIH/NIDA Contract No. HHSN271201300004C to JWB; R01 DA03706 to HH; R01s DA16752, DA18691, DA15732 and DA9253 to SH; P50 CA84724, K05 CA139871 and P50 DA19706 to TBB; R01s CA71358 and DA11170 to GES; and PGRN U01 DA20830 to NLB (2005-2010), and to RFT and CL (2010-2015)]; a grant from the University of California Tobacco Related Diseases Research Program (7PT2004 to NLB); by the Centre for Addiction and Mental Health (RFT); and by an endowed Chair in Addictions (RFT).

Clinical trials (NCT Trial IDs) 00301145, 01621009, 01621022 and 00332644 were funded by the National Cancer Institute, 00087880 and 00086385 were funded by the National Institute of Drug Abuse, and 00326781 and 00322205 were funded by the National Cancer Institute and by the National Institute of Drug Abuse.

Varenicline and nominal support for recruiting clinical trial 00301145 participants was provided by Pfizer.

GlaxoSmithKline provided medication for clinical trials 01621022 and 00332644.

Keywords:

  • Science & Technology
  • Multidisciplinary Sciences
  • Science & Technology - Other Topics
  • CONTROLLED CLINICAL-TRIAL
  • TREATMENT-SEEKING SMOKERS
  • HUMAN LIVER-MICROSOMES
  • SMOKING-CESSATION
  • REPLACEMENT THERAPY
  • CYP2B6 GENOTYPE
  • FAGERSTROM TEST
  • C-OXIDATION
  • TOBACCO USE
  • BUPROPION
  • Drug metabolism
  • Nicotine
  • Lung and intrathoracic tumors
  • Drug therapy
  • Smoking habits
  • Meta-analysis
  • Enzyme metabolism
  • Nicotine replacement

Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption

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Journal Title:

PLoS ONE

Volume:

Volume 10, Number 7

Publisher:

, Pages e0126113-e0126113

Type of Work:

Article | Final Publisher PDF

Abstract:

The Nicotine Metabolite Ratio (NMR, ratio of trans-3'-hydroxycotinine and cotinine), has previously been associated with CYP2A6 activity, response to smoking cessation treatments, and cigarette consumption. We searched for drug metabolizing enzyme and transporter (DMET) gene variation associated with the NMR and prospective abstinence in 2,946 participants of laboratory studies of nicotine metabolism and of clinical trials of smoking cessation therapies. Stage I was a meta-analysis of the association of 507 common single nucleotide polymorphisms (SNPs) at 173 DMET genes with the NMR in 449 participants of two laboratory studies. Nominally significant associations were identified in ten genes after adjustment for intragenic SNPs; CYP2A6 and two CYP2A6 SNPs attained experiment-wide significance adjusted for correlated SNPs (CYP2A6 P<inf>ACT</inf>=4.1E-7, rs4803381 P<inf>ACT</inf>=4.5E-5, rs1137115, P<inf>ACT</inf>=1.2E-3). Stage II was mega-regression analyses of 10 DMET SNPs with pretreatment NMR and prospective abstinence in up to 2,497 participants from eight trials. rs4803381 and rs1137115 SNPs were associated with pretreatment NMR at genome-wide significance. In post-hoc analyses of CYP2A6 SNPs, we observed nominally significant association with: abstinence in one pharmacotherapy arm; cigarette consumption among all trial participants; and lung cancer in four case:control studies. CYP2A6 minor alleles were associated with reduced NMR, CPD, and lung cancer risk. We confirmed the major role that CYP2A6 plays in nicotine metabolism, and made novel findings with respect to genome-wide significance and associations with CPD, abstinence and lung cancer risk. Additional multivariate analyses with patient variables and genetic modeling will improve prediction of nicotine metabolism, disease risk and smoking cessation treatment prognosis.

Copyright information:

© 2015 Bergen et al.

This is an Open Access work distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).
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