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.
Bibliographical noteFunding Information:
COGA was supported by U10AA008401 (NIAAA) and COGEND was supported by P01CA089392 (NCI). E.O was supported by T32GM07200 (NIGMS), UL1TR000448 (NCATS), TL1TR000449 (NCATS) and F30AA023685 (NIAAA). S.H was supported by K08DA032680 (NIDA). L.J.B was supported by R01DA036583 (NIDA) and P30CA091842 (NCI). LJB, AG, and the spouse of NLS are listed as inventors on Issued U.S. Patent 8,080,371, ?Markers for Addiction? covering the use of certain SNPs in determining the diagnosis, prognosis, and treatment of addiction. JN is an investigator for Assurex and an investigator and consultant for Janssen. The other authors declare no conflict of interest. LJB, AG, JPR, DMD, HJE, VMH. JRK, SK, JN, BP, MAS and JAT contributed to the conception and design of COGA. LJB, AG, JPR, EOJ, NLS, NB, DH and JS contributed to the conception and design of COGEND. AB and JAT managed the DNA biorepository. JPB performed the genotyping. SB cleaned the genetic data. EO performed the statistical analyses. All authors assisted with analysis design and interpretation of findings. EO and LJB drafted the manuscript. All authors critically reviewed the manuscript, provided important intellectual feedback and approved the manuscript.
COGA was supported by U10AA008401 (NIAAA) and COGEND was supported by P01CA089392 (NCI). E.O was supported by T32GM07200 (NIGMS), UL1TR000448 (NCATS), TL1TR000449 (NCATS) and F30AA023685 (NIAAA). S.H was supported by K08DA032680 (NIDA). L.J.B was supported by R01DA036583 (NIDA) and P30CA091842 (NCI).
© 2016 Society for the Study of Addiction
- nicotine dependence
- young adults