Common human genetic variants of APOE impact murine COVID-19 mortality

Abstract

Clinical outcomes of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are highly heterogeneous, ranging from asymptomatic infection to lethal coronavirus disease 2019 (COVID-19). The factors underlying this heterogeneity remain insufficiently understood. Genetic association studies have suggested that genetic variants contribute to the heterogeneity of COVID-19 outcomes, but the underlying potential causal mechanisms are insufficiently understood. Here we show that common variants of the Apolipoprotein E (APOE) gene, homozygous in approximately 3% of the world’s population1 and associated with Alzheimer’s disease, atherosclerosis and anti-tumor immunity2–5, impact COVID-19 outcome in a mouse model that recapitulates increased susceptibility conferred by male sex and advanced age. Mice bearing the APOE2 or APOE4 variant exhibited rapid disease progression and poor survival outcomes relative to mice bearing the most prevalent APOE3 allele. APOE2 and APOE4 mice exhibited increased viral loads as well as suppressed adaptive immune responses early after infection. In vitro assays demonstrated increased infection in the presence of APOE2 and APOE4 relative to APOE3, indicating that differential outcomes are mediated by differential effects of APOE variants on both viral infection and antiviral immunity. Consistent with these in vivo findings in mice, APOE genotype was associated with survival in SARS-CoV-2 infected patients in the UK Biobank (candidate variant analysis, P = 2.6×10-7). Our findings suggest APOE genotype to partially explain the heterogeneity of COVID-19 outcomes and warrant prospective studies to assess APOE genotyping as a means of identifying patients at high risk for adverse outcomes.

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Author notes

  1. These authors contributed equally: Mira A. Patel, Jana Bilanovic

Authors and Affiliations

  1. Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA

    Benjamin N. Ostendorf, Mira A. Patel, Jana Bilanovic & Sohail F. Tavazoie

  2. Department of Hematology, Oncology, and Tumor Immunology and Berlin Institute of Health, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Benjamin N. Ostendorf

  3. Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Benjamin N. Ostendorf

  4. Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA

    H.-Heinrich Hoffmann & Charles M. Rice

  5. Laboratory of Comparative Pathology, Weill Cornell Medicine, Memorial Sloan Kettering Cancer Center, and Rockefeller University, New York, NY, USA

    Sebastian E. Carrasco

Corresponding authors

Correspondence to
Benjamin N. Ostendorf or Sohail F. Tavazoie.

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Ostendorf, B.N., Patel, M.A., Bilanovic, J. et al. Common human genetic variants of APOE impact murine COVID-19 mortality.
Nature (2022). https://doi.org/10.1038/s41586-022-05344-2

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  • DOI: https://doi.org/10.1038/s41586-022-05344-2

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