title: CYP2A6 metabolism in the development of smoking behaviors in young adults.
abstract: Cytochrome P450 2A6 (CYP2A6) encodes the enzyme responsible for the majority of nicotine metabolism. Previous studies support that slow metabolizers smoke fewer cigarettes once nicotine dependent but provide conflicting results on the role of CYP2A6 in the development of dependence. By focusing on the critical period of young adulthood, this study examines the relationship of CYP2A6 variation and smoking milestones. A total of 1209 European American young adults enrolled in the Collaborative Study on the Genetics of Alcoholism were genotyped for CYP2A6 variants to calculate a previously well-validated metric that estimates nicotine metabolism. This metric was not associated with the transition from never smoking to smoking initiation nor with the transition from initiation to daily smoking (P > 0.4). But among young adults who had become daily smokers (n = 506), decreased metabolism was associated with increased risk of nicotine dependence (P = 0.03) (defined as Fagerström Test for Nicotine Dependence score ≥4). This finding was replicated in the Collaborative Genetic Study of Nicotine Dependence with 335 young adult daily smokers (P = 0.02). Secondary meta-analysis indicated that slow metabolizers had a 53 percent increased odds (OR = 1.53, 95 percent CI 1.11-2.11, P = 0.009) of developing nicotine dependence compared with normal metabolizers. Furthermore, secondary analyses examining four-level response of time to first cigarette after waking (>60, 31-60, 6-30, ≤5 minutes) demonstrated a robust effect of the metabolism metric in Collaborative Study on the Genetics of Alcoholism (P = 0.03) and Collaborative Genetic Study of Nicotine Dependence (P = 0.004), illustrating the important role of this measure of dependence. These findings highlight the complex role of CYP2A6 variation across different developmental stages of smoking behaviors.
authors.affiliation: Child Study Center and Department of Psychiatry, Yale University School of Medicine, New Haven, CT, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Olfson
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.|Department of Anesthesiology, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Bloom
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Bertelsen
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Budde
authors.affiliation: Department of Epidemiology and Biostatistics, Michigan State University, East Lansing, MI, USA.
authors.forename: Naomi
authors.initials: N
authors.lastname: Breslau
authors.affiliation: Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Brooks
authors.affiliation: Department of Medicine, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Culverhouse
authors.affiliation: Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA.
authors.forename: Grace
authors.initials: G
authors.lastname: Chan
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Li-Shiun
authors.initials: LS
authors.lastname: Chen
authors.affiliation: Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chorlian
authors.affiliation: Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Danielle M
authors.initials: DM
authors.lastname: Dick
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Hartz
authors.affiliation: Department of Psychiatry, University of Minnesota, Minneapolis, MN, USA.
authors.forename: Dorothy
authors.initials: D
authors.lastname: Hatsukami
authors.affiliation: Department of Psychiatry, University of Connecticut School of Medicine, Farmington, CT, USA.
authors.forename: Victor M
authors.initials: VM
authors.lastname: Hesselbrock
authors.affiliation: Behavioral Health Epidemiology Program, RTI International, Research Triangle Park, NC, USA.
authors.forename: Eric O
authors.initials: EO
authors.lastname: Johnson
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Kramer
authors.affiliation: Department of Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Kuperman
authors.affiliation: Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Jacquelyn L
authors.initials: JL
authors.lastname: Meyers
authors.affiliation: Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, USA.
authors.forename: John
authors.initials: J
authors.lastname: Nurnberger
authors.affiliation: Department of Psychiatry and Behavioral Sciences, SUNY Downstate Medical Center, Brooklyn, NY, USA.
authors.forename: Bernice
authors.initials: B
authors.lastname: Porjesz
authors.affiliation: Department of Genetics, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Saccone
authors.affiliation: Department of Psychiatry, University of California, San Diego Medical School, San Diego, CA, USA.
authors.forename: Marc A
authors.initials: MA
authors.lastname: Schuckit
authors.affiliation: Institute for Behavioral Genetics, University of Colorado, Boulder, CO, USA.
authors.forename: Jerry
authors.initials: J
authors.lastname: Stitzel
authors.affiliation: Department of Genetics and the Human Genetics Institute of New Jersey, Rutgers University, Piscataway, NJ, USA.
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: John P
authors.initials: JP
authors.lastname: Rice
authors.affiliation: Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.affiliation: Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Bierut
mesh_terms: D000328:Adult; D000073865:Cigarette Smoking / Q000235:genetics*; D065637:Cytochrome P-450 CYP2A6 / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D014029:Tobacco Use Disorder / Q000235:genetics*; D044465:White People / Q000235:genetics; D055815:Young Adult
chemical_list: C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6
keywords: CYP2A6; genetics; nicotine dependence; smoking; young adults