Science and Research

ELF5 is a potential respiratory epithelial cell-specific risk gene for severe COVID-19

Despite two years of intense global research activity, host genetic factors that predispose to a poorer prognosis of COVID-19 infection remain poorly understood. Here, we prioritise eight robust (e.g., ELF5) or suggestive but unreported (e.g., RAB2A) candidate protein mediators of COVID-19 outcomes by integrating results from the COVID-19 Host Genetics Initiative with population-based plasma proteomics using statistical colocalisation. The transcription factor ELF5 (ELF5) shows robust and directionally consistent associations across different outcome definitions, including a >4-fold higher risk (odds ratio: 4.88; 95%-CI: 2.47-9.63; p-value < 5.0 × 10(-6)) for severe COVID-19 per 1 s.d. higher genetically predicted plasma ELF5. We show that ELF5 is specifically expressed in epithelial cells of the respiratory system, such as secretory and alveolar type 2 cells, using single-cell RNA sequencing and immunohistochemistry. These cells are also likely targets of SARS-CoV-2 by colocalisation with key host factors, including ACE2 and TMPRSS2. In summary, large-scale human genetic studies together with gene expression at single-cell resolution highlight ELF5 as a risk gene for severe COVID-19, supporting a role of epithelial cells of the respiratory system in the adverse host response to SARS-CoV-2.
  • Pietzner, M.
  • Chua, R. L.
  • Wheeler, E.
  • Jechow, K.
  • Willett, J. D. S.
  • Radbruch, H.
  • Trump, S.
  • Heidecker, B.
  • Zeberg, H.
  • Heppner, F. L.
  • Eils, R.
  • Mall, M. A.
  • Richards, J. B.
  • Sander, L. E.
  • Lehmann, I.
  • Lukassen, S.
  • Wareham, N. J.
  • Conrad, C.
  • Langenberg, C.

Keywords

  • Angiotensin-Converting Enzyme 2/genetics
  • *COVID-19/genetics
  • DNA-Binding Proteins/genetics
  • Epithelial Cells/metabolism
  • Humans
  • Peptidyl-Dipeptidase A/metabolism
  • Respiratory System
  • SARS-CoV-2
  • Transcription Factors/genetics
Publication details
DOI: 10.1038/s41467-022-31999-6
Journal: Nat Commun
Pages: 4484 
Number: 1
Work Type: Original
Location: Assoziierter Partner
Disease Area: PALI
Partner / Member: BIH
Access-Number: 35970849

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