Nicotine Metabolism Predicted by CYP2A6 Genotypes in Relation to Smoking Cessation: A Systematic Review

Abstract

Introduction: Identifying genetic factors associated with smoking cessation could inform precision cessation interventions. Of major interest is genetic variation in nicotine metabolism, largely predicted by CYP2A6 variations.

Aims and methods: We conducted a systematic literature review to summarize the population-based evidence of the association between CYP2A6 and smoking cessation. In the 12 studies meeting the inclusion criteria, the known functional metabolic effect of CYP2A6 variants was used to classify nicotine metabolism as normal (>75% metabolic activity), intermediate (50.1%-75% activity), slow (25%-50% activity), and poor (<25% activity). Summary odds ratios of smoking cessation were calculated across metabolic groups, stratified by ancestry and whether participants received pharmacotherapy or placebo/no treatment.

Results: Among untreated people of European ancestry (n = 4 studies), those with CYP2A6 reduced metabolism were more likely to quit smoking than those with normal metabolism (Summary OR = 2.05, 95% CI 1.23 to 3.42) and the likelihood of cessation increased as nicotine metabolism decreased. Nicotine replacement therapy attenuated the association at end-of-treatment, while bupropion modified the association such that intermediate/slow metabolizers were less likely to quit than normal metabolizers (Summary OR = 0.86, 95% CI 0.79 to 0.94). Among untreated Asian people (n = 3 studies), results differed compared with those with European ancestry: those with slow metabolism were less likely to have quit smoking than normal metabolizers (Summary OR = 0.52, 95% CI 0.38 to 0.71). Evidence for people of African ancestry (n = 1 study) suggested the CYP2A6 association with cessation may differ compared with those of European ancestry.

Conclusions and implications: Most studies included in this review were of European ancestry populations; these showed slower nicotine metabolism was associated with increased likelihood of smoking cessation in a dose-related manner. Pharmacotherapy appeared to attenuate or modify this association among people of European ancestry, but it is unclear whether the change in the association remains consistent after treatment ceases. This finding has implications for precision medicine cessation interventions. Based on only a few studies of people of Asian or African ancestry, the association between CYP2A6 variants and cessation may differ from that observed among those of European ancestry, but more evidence is needed.

Figure 1.

Summary of search process in systemic review of CYP2A6 variation in relation to smoking cessation in observational studies and clinical trials of smoking cessation interventions.

Figure 2.

CYP2A6 results. (a) European ancestry with no pharmaceutical treatment or in a placebo arm, (b) European ancestry in pharmaceutical treatments groups, (c) Asian ancestry, (d) African ancestry (results are for women). NM = normal metabolism, IM = intermediate metabolism, SM = slow metabolism, PM = poor metabolism, EOT = end of treatment, NRT = nicotine replacement therapy. *Significant heterogeneity.