title: Drug Metabolizing Enzyme and Transporter Gene Variation, Nicotine Metabolism, Prospective Abstinence, and Cigarette Consumption.
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.
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, California, United States of America.
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Bergen
authors.affiliation: Academic Research Systems, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Martha
authors.initials: M
authors.lastname: Michel
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, California, United States of America.
authors.forename: Denise
authors.initials: D
authors.lastname: Nishita
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, California, United States of America.
authors.forename: Ruth
authors.initials: R
authors.lastname: Krasnow
authors.affiliation: Center for Health Sciences, SRI International, Menlo Park, California, United States of America.
authors.forename: Harold S
authors.initials: HS
authors.lastname: Javitz
authors.affiliation: Department of Human Genetics, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Karen N
authors.initials: KN
authors.lastname: Conneely
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Christina N
authors.initials: CN
authors.lastname: Lessov-Schlaggar
authors.affiliation: Oregon Research Institute, Eugene, Oregon, United States of America.
authors.forename: Hyman
authors.initials: H
authors.lastname: Hops
authors.affiliation: Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Andy Z X
authors.initials: AZ
authors.lastname: Zhu
authors.affiliation: BioRealm, LLC, Monument, Colorado, United States of America.
authors.forename: James W
authors.initials: JW
authors.lastname: Baurley
authors.affiliation: Group Health Research Institute, Seattle, Washington, United States of America.
authors.forename: Jennifer B
authors.initials: JB
authors.lastname: McClure
authors.affiliation: Department of Psychiatry, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Hall
authors.affiliation: Center for Tobacco Research and Intervention, Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, United States of America.
authors.forename: Timothy B
authors.initials: TB
authors.lastname: Baker
authors.affiliation: Department of Preventive Medicine, University of Southern California, Los Angeles, California, United States of America.
authors.forename: David V
authors.initials: DV
authors.lastname: Conti
authors.affiliation: Departments of Medicine and of Bioengineering & Therapeutic Sciences, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Benowitz
authors.affiliation: Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
authors.forename: Caryn
authors.initials: C
authors.lastname: Lerman
authors.affiliation: 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.
authors.forename: Rachel F
authors.initials: RF
authors.lastname: Tyndale
authors.affiliation: 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.
authors.forename: Gary E
authors.initials: GE
authors.lastname: Swan
mesh_terms: D000328:Adult; D000483:Alleles; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics* / Q000378:metabolism; D005260:Female; D056726:Genetic Association Studies; D014644:Genetic Variation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009538:Nicotine / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D012907:Smoking; D016540:Smoking Cessation
chemical_list: D009538:Nicotine; D065637:Cytochrome P-450 CYP2A6