Influence of <i>CYP2A6</i> genetic variation, nicotine dependence severity, and treatment on smoking cessation success

Chenoweth, Meghan J and Lerman, Caryn and Knight, Jo and Tyndale, Rachel F (2023) Influence of <i>CYP2A6</i> genetic variation, nicotine dependence severity, and treatment on smoking cessation success. Nicotine and Tobacco Research, 25 (6). pp. 1207-1211. ISSN 1462-2203

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Background Genetic variation in CYP2A6, the major nicotine metabolizing enzyme, is associated with nicotine dependence and smoking cessation. Nicotine dependence severity also predicts smoking cessation. Our goals were to determine how CYP2A6 variation and nicotine dependence alter smoking cessation, and whether dependence could refine CYP2A6-based treatment recommendations. Methods Adult smokers treated for 12 weeks with placebo, nicotine patch, or varenicline (NCT01314001) were grouped as CYP2A6 normal (n=567) or slow (n=432) nicotine metabolizers based on a CYP2A6 weighted genetic risk score. FTND scores were measured at baseline and biochemically-verified smoking cessation was assessed at end-of-treatment. Results Dependence neither mediated nor moderated an association between CYP2A6 variation and smoking cessation overall, within any treatment arm, or after stratifying by ancestry (n=591 European, n=408 African ancestry) or sex (n=444 women, n=555 men). In within-treatment analyses, the mediation effect odds ratio (OR) ranged from 0.95-1.00 and the bias-corrected 95% confidence interval contained 1. Moderation (i.e., interaction) effect ORs ranged from 0.88-1.61 (P=0.397-0.828). For CYP2A6 normal metabolizers, quit rates on varenicline were similar for those with high (41.1%) and low (43.4%) dependence, while quit rates were lower for those with high vs. low dependence on both patch (16.5 vs. 29.7%) and placebo (8.9 vs. 18.5%). CYP2A6 slow metabolizers with high vs. low dependence had lower quit rates in all three treatment arms. Conclusions While nicotine dependence severity neither mediated nor moderated CYP2A6 associations with smoking cessation, incorporating information on dependence may optimize the choice of smoking cessation treatment aid in CYP2A6 normal and slow metabolizers. Implications Variation in CYP2A6 and nicotine dependence severity alter smoking cessation success. Our findings suggest that while nicotine dependence severity is unlikely to mediate or moderate CYP2A6 associations with cessation, incorporating patient information on both CYP2A6 and nicotine dependence severity may lead to improved smoking cessation strategies.

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Journal Article
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Nicotine and Tobacco Research
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This is a pre-copy-editing, author-produced PDF of an article accepted for publication in Nicotine and Tobacco Research following peer review. The definitive publisher-authenticated version Meghan J Chenoweth, PhD and others, Influence of CYP2A6 Genetic Variation, Nicotine Dependence Severity, and Treatment on Smoking Cessation Success, Nicotine & Tobacco Research, Volume 25, Issue 6, June 2023, Pages 1207–1211, is available online at:
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20 Mar 2023 11:20
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19 Sep 2023 02:59