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Genetic meta-analysis of cancer diagnosis following statin use identifies new associations and implicates human leukocyte antigen (HLA) in women

The Pharmacogenomics Journal volume 21, pages 446–457 (2021)Cite this article

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Abstract

We sought to perform a genomic evaluation of the risk of incident cancer in statin users, free of cancer at study entry. Patients who previously participated in two phase IV trials (TNT and IDEAL) with genetic data were used (npooled = 11,196). A GWAS meta-analysis using Cox modeling for the prediction of incident cancer was conducted in the pooled cohort and sex-stratified. rs13210472 (near HLA-DOA gene) was associated with higher risk of incident cancer amongst women with prevalent coronary artery disease (CAD) taking statins (hazard ratio [HR]: 2.66, 95% confidence interval [CI]: 1.88–3.76, P = 3.5 × 10−8). Using the UK Biobank and focusing exclusively on women statin users with CAD (nfemale = 2952), rs13210472 remained significantly associated with incident cancer (HR: 1.71, 95% CI: 1.14–2.56, P = 9.0 × 10−3). The association was not observed in non-statin users. In this genetic meta-analysis, we have identified a variant in women statin users with prevalent CAD that was associated with incident cancer, possibly implicating the human leukocyte antigen pathway.

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Fig. 1: Manhattan plot of the genome-wide association meta-analysis analysis of genetic variants of minor allele frequency ≥ 1% for time to occurrence of cancer using a Cox proportional hazards regression from the TNT and IDEAL cohorts.
Fig. 2: Diagram summarizing the associations observed between rs13210472 and incident cancer within the replication cohort based on multivariable Cox regression models.

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Acknowledgements

The TNT and IDEAL trials were sponsored by Pfizer. Pfizer granted access to data but had no role in the design of the current study, the drafting of this report, or the decision to submit these analyses for publication.

Funding

The current study was funded in part by grants from Genome Canada and Genome Quebec and the Canadian Institutes of Health Research (CIHR). This research has been conducted using the UK Biobank Resource under Application Number 20168. MS is supported by a scholarship from FRQS. M-AL is supported by a scholarship from the CIHR. M-PD holds the Canada Research Chair in Precision Medicine Data Analysis, J-CT holds the Canada Research Chair in Personalized Medicine.

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  1. These authors contributed equally: Jean-Claude Tardif, Marie-Pierre Dubé

Authors and Affiliations

  1. Université de Montréal Beaulieu-Saucier Pharmacogenomics Center, Montreal, QC, Canada

    Maxine Sun, Audrey Lemaçon, Marc-André Legault, Géraldine Asselin, Sylvie Provost, Amina Barhdadi, Diane Valois, Ian Mongrain & Marie-Pierre Dubé

  2. Montreal Heart Institute, Montreal, QC, Canada

    Maxine Sun, Audrey Lemaçon, Marc-André Legault, Géraldine Asselin, Sylvie Provost, Amina Barhdadi, Yassamin Feroz Zada, Diane Valois, Ian Mongrain, Jean-Claude Tardif & Marie-Pierre Dubé

  3. Faculty of Medicine, Université de Montréal, Montreal, QC, Canada

    Maxine Sun, Marc-André Legault, Jean-Claude Tardif & Marie-Pierre Dubé

  4. Centre de Bioinformatique, Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, Paris, France

    Hugues Aschard

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Correspondence to Marie-Pierre Dubé.

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Conflict of interest

M-PD has received research support from AstraZeneca, DalCor, Pfizer, GSK, Servier and honoraria from DalCor, Servier, and GSK. J-CT has received research support from Amarin, AstraZeneca, DalCor, Eli-Lilly, Hoffmann-LaRoche, Merck, Pfizer, Sanofi and Servier, and honoraria (to his institution) from Hoffmann-LaRoche, Pfizer, Servier, and Valeant. J-CT and M-PD have an equity interest in DalCor. MS has received grant funding from Pfizer, BMS, and Exelixis. All other authors have no conflicts of interest or disclosures to state.

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Sun, M., Lemaçon, A., Legault, MA. et al. Genetic meta-analysis of cancer diagnosis following statin use identifies new associations and implicates human leukocyte antigen (HLA) in women. Pharmacogenomics J 21, 446–457 (2021). https://doi.org/10.1038/s41397-021-00221-z

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