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Associating CYP2A6 structural variants with ovarian and lung cancer risk in the UK Biobank: replication and extension

European Journal of Human Genetics volume 32, pages 357–360 (2024)Cite this article

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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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Fig. 1: Schematic of computationally-inferred deletion regions and comparison to known CYP2A6 SVs.
Fig. 2: SV imputation reference panel creation flowchart.
Fig. 3: CYP2A6 SV alleles and risk for ovarian or lung cancer.

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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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Authors and Affiliations

  1. Department of Pharmacology & Toxicology, University of Toronto, 1 King’s College Circle, Toronto, ON, M5S 1A8, Canada

    Alec W. R. Langlois, Meghan J. Chenoweth & Rachel F. Tyndale

  2. Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, 100 Stokes Street, Toronto, ON, M6J 1H4, Canada

    Alec W. R. Langlois, Jennie G. Pouget, Meghan J. Chenoweth & Rachel F. Tyndale

  3. Department of Psychiatry, University of Toronto, 250 College Street, Toronto, ON, M5T 1R8, Canada

    Jennie G. Pouget, Meghan J. Chenoweth & Rachel F. Tyndale

  4. Data Science Institute and Medical School, Lancaster University, Lancaster, UK

    Jo Knight

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  1. Alec W. R. Langlois
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  2. Jennie G. Pouget
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  5. Rachel F. Tyndale
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Contributions

AWRL performed analyses and drafted the manuscript; AWRL, JGP, JK, MJC, and RFT conceived of the research and reviewed the manuscript.

Corresponding author

Correspondence to Rachel F. Tyndale.

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The authors declare no competing interests.

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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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