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. 2018 Jan;23(1):437-447.
doi: 10.1111/adb.12477. Epub 2016 Dec 29.

CYP2A6 metabolism in the development of smoking behaviors in young adults

Emily Olfson  1 , Joseph Bloom  2   3 , Sarah Bertelsen  4 , John P Budde  2 , Naomi Breslau  5 , Andrew Brooks  6 , Robert Culverhouse  7 , Grace Chan  8 , Li-Shiun Chen  2 , David Chorlian  9 , Danielle M Dick  10 , Howard J Edenberg  11 , Sarah Hartz  2 , Dorothy Hatsukami  12 , Victor M Hesselbrock  8 , Eric O Johnson  13 , John R Kramer  14 , Samuel Kuperman  14 , Jacquelyn L Meyers  9 , John Nurnberger  15 , Bernice Porjesz  9 , Nancy L Saccone  16 , Marc A Schuckit  17 , Jerry Stitzel  18 , Jay A Tischfield  6 , John P Rice  2 , Alison Goate  4 , Laura J Bierut  2
Affiliations

CYP2A6 metabolism in the development of smoking behaviors in young adults

Emily Olfson et al. Addict Biol. 2018 Jan.

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.

Keywords: CYP2A6; genetics; nicotine dependence; smoking; young adults.

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Conflict of interest statement

Disclosure/Conflict of Interest:

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.

Figures

Figure 1
Figure 1
Primary COGA sample selection.
Figure 2
Figure 2
Association between predicted metabolism and smoking behaviors in two studies of European American young adult daily smokers. Error bars reflect standard errors adjusted for sample size.
Figure 3
Figure 3
A theoretical framework of the development of smoking behaviors in relation to CYP2A6 variation. Steps 1 and 2 are supported by this paper and previous studies. Steps 3 and 4 are supported by previous studies (reviewed in Benowitz, 2008; Malaiyandi et al., 2005)
See this image and copyright information in PMC

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