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PLoS One. 2015 Jul 1;10(7):e0126113. doi: 10.1371/journal.pone.0126113. eCollection 2015.

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

Author information

1
Center for Health Sciences, SRI International, Menlo Park, California, United States of America.
2
Academic Research Systems, University of California San Francisco, San Francisco, California, United States of America.
3
Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
4
Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America.
5
Oregon Research Institute, Eugene, Oregon, United States of America.
6
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
7
BioRealm, LLC, Monument, Colorado, United States of America.
8
Group Health Research Institute, Seattle, Washington, United States of America.
9
Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.
10
Center for Tobacco Research and Intervention, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
11
Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
12
Departments of Medicine and of Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
13
Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
14
Cambell Family Mental Health Research Institute, Centre for Addiction and Mental Health, and Departments of Psychiatry, and of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
15
Oregon Research Institute, Eugene, Oregon, United States of America; Stanford Prevention Research Center, Department of Medicine, Stanford University School of Medicine, Palo Alto, California, United States of America.

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 PACT=4.1E-7, rs4803381 PACT=4.5E-5, rs1137115, PACT=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.

PMID:
26132489
PMCID:
PMC4488893
DOI:
10.1371/journal.pone.0126113
[Indexed for MEDLINE]
Free PMC Article

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