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Common human genetic variants of APOE impact murine COVID-19 mortality.
Ostendorf, Benjamin N; Patel, Mira A; Bilanovic, Jana; Hoffmann, H-Heinrich; Carrasco, Sebastian E; Rice, Charles M; Tavazoie, Sohail F.
  • Ostendorf BN; Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA. bostendorf@rockefeller.edu.
  • Patel MA; Department of Hematology, Oncology, and Tumor Immunology, Charité-Universitätsmedizin Berlin, Berlin, Germany. bostendorf@rockefeller.edu.
  • Bilanovic J; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany. bostendorf@rockefeller.edu.
  • Hoffmann HH; Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany. bostendorf@rockefeller.edu.
  • Carrasco SE; Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA.
  • Rice CM; Laboratory of Systems Cancer Biology, The Rockefeller University, New York, NY, USA.
  • Tavazoie SF; Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY, USA.
Nature ; 611(7935): 346-351, 2022 11.
Article in English | MEDLINE | ID: covidwho-2036837
ABSTRACT
Clinical outcomes of severe acute respiratory syndrome 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-tumour immunity2-5, affect 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, our results also show that APOE genotype is associated with survival in patients infected with SARS-CoV-2 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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Full text: Available Collection: International databases Database: MEDLINE Main subject: Apolipoproteins E / Mice, Transgenic / Human Genetics / SARS-CoV-2 / COVID-19 Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study Topics: Variants Limits: Animals / Humans / Male Language: English Journal: Nature Year: 2022 Document Type: Article Affiliation country: S41586-022-05344-2

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Apolipoproteins E / Mice, Transgenic / Human Genetics / SARS-CoV-2 / COVID-19 Type of study: Cohort study / Experimental Studies / Observational study / Prognostic study Topics: Variants Limits: Animals / Humans / Male Language: English Journal: Nature Year: 2022 Document Type: Article Affiliation country: S41586-022-05344-2