Faster CYP2A6 increases COPD and lung cancer risk by increasing smoking quantity : a mediated mendelian randomization and observational mediation study

Giratallah, Haidy and Chenoweth, Meghan J. and Lerman, Caryn and Knight, Jo and Tyndale, Rachel F. (2026) Faster CYP2A6 increases COPD and lung cancer risk by increasing smoking quantity : a mediated mendelian randomization and observational mediation study. Respiratory Research. ISSN 1465-9921

Abstract

Background Genetic variation in CYP2A6, an enzyme which inactivates nicotine and activates nitrosamines, alters smoking behaviours and was associated with chronic obstructive pulmonary disease (COPD) and lung cancer (LC) in a phenome-wide association study. Research questions Does smoking quantity mediate the association between CYP2A6 and the risk for COPD and LC? Does the extent of mediation differ between the diseases? Methods We implemented two-step two-sample mediated Mendelian Randomization (MR) and observational mediation analyses. CYP2A6 activity was instrumented using a CYP2A6 genetic score. We tested pack-years (chronic smoking exposure), cigarettes per day (CPD; self-reported), and the summation of nicotine’s main metabolites, cotinine, and trans-3’-hydroxycotinine (COT+3HC; nicotine intake biomarker) as quantity measures among current smokers. We sourced smoking quantity genetic instruments for MR from genome-wide significant summary statistics. This research was conducted using the UK Biobank Resource. Results All three smoking quantity measures significantly mediated the effects of CYP2A6 activity on COPD and LC risk in forward mediated MR (p values < 0.05). Given the many assumptions of MR, this provides only a potential direction of effect. Smoking quantity measures mediated a large proportion of the COPD risk but less for LC. In reverse mediated MR (i.e., negative control), CYP2A6 activity did not mediate smoking quantity effects on COPD and LC. Interpretation Mediated MR and observational mediation analyses together supported a mechanistic role of faster CYP2A6 influencing smoking quantity increase, which increases COPD and LC risk. The observational mediation analyses suggest additional mechanisms may be involved in CYP2A6’s impact on LC.