| Title: | Faster CYP2A6 increases COPD and lung cancer risk by increasing smoking quantity: a mediated mendelian randomization and observational mediation study |
| Journal: | Respiratory Research |
| Published: | 1 Jun 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/42219484/ |
| DOI: | https://doi.org/10.1186/s12931-026-03747-7 |
Publication 19901
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Abstract
BackgroundGenetic 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 questionsDoes smoking quantity mediate the association between CYP2A6 and the risk for COPD and LC? Does the extent of mediation differ between the diseases?MethodsWe 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.ResultsAll 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.InterpretationMediated 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.</p>
5 Authors
- Haidy Giratallah
- Meghan J. Chenoweth
- Caryn Lerman
- Jo Knight
- Rachel F. Tyndale
1 Application
| Application ID | Title |
|---|---|
| 55371 | Phenome-wide association and mendelian randomization studies of a weighted genetic risk score (wGRS) of CYP2A6, the gene for a nicotine and nitrosamine metabolizing enzyme |
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