Abstract
CYP2A6 is a polymorphic enzyme that inactivates nicotine; structural variants (SVs) include gene deletions and hybrids with the neighboring pseudogene CYP2A7. Two studies found that CYP2A7 deletions were associated with ovarian cancer risk. Using their methodology, we aimed to characterize CYP2A6 SVs (which may be misidentified by prediction software as CYP2A7 SVs), then assess CYP2A6 SV-associated risk for ovarian cancer, and extend analyses to lung cancer. An updated reference panel was created to impute CYP2A6 SVs from UK Biobank array data. Logistic regression models analyzed the association between CYP2A6 SVs and cancer risk, adjusting for covariates. Software-predicted CYP2A7 deletions were concordant with known CYP2A6 SVs. Deleterious CYP2A6 SVs were not associated with ovarian cancer (OR = 1.06; 95% CI: 0.80–1.37; p = 0.7) but did reduce the risk of lung cancer (OR = 0.44; 95% CI: 0.29–0.64; p < 0.0001), and a lung cancer subtype. Replication of known lung cancer associations indicates the validity of array-based SV analyses.
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Data availability
Data from participants is accessible in the UK Biobank (datafields: 20116, 21022, 22001, 22006, 22418, 41270, 41271); reference panel data is not publicly available due to individual privacy concerns.
Code availability
Available upon request.
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Acknowledgements
We acknowledge the work of Haidy Giratallah in obtaining and formatting UK Biobank data for analysis.
Funding
This work was funded by a Canadian Institutes of Health Research (CIHR) Project grant (PJY-159710) and Foundation grant (FDN-154294), National Institutes of Health (NIH) Grant PGRN DA020830, and a Canada Research Chair in Pharmacogenomics (Tyndale).
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AWRL performed analyses and drafted the manuscript; AWRL, JGP, JK, MJC, and RFT conceived of the research and reviewed the manuscript.
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Use of genetic data from imputation reference panel participants was approved at the University of Toronto and clinical trial sites where genetic material was collected.
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Langlois, A.W.R., Pouget, J.G., Knight, J. et al. Associating CYP2A6 structural variants with ovarian and lung cancer risk in the UK Biobank: replication and extension. Eur J Hum Genet 32, 357–360 (2024). https://doi.org/10.1038/s41431-023-01518-2
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DOI: https://doi.org/10.1038/s41431-023-01518-2
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