Human ACE2 receptor polymorphisms and altered susceptibility to SARS-CoV-2

  1. Kushal Suryamohan
  2. Devan Diwanji
  3. Eric W. Stawiski
  4. Ravi Gupta
  5. Shane Miersch
  6. Jiang Liu
  7. Chao Chen
  8. Ying-Ping Jiang
  9. Frederic A. Fellouse
  10. J. Fah Sathirapongsasuti
  11. Patrick K. Albers
  12. Tanneeru Deepak
  13. Reza Saberianfar
  14. Aakrosh Ratan
  15. Gavin Washburn
  16. Monika Mis
  17. Devi Santhosh
  18. Sneha Somasekar
  19. G. H. Hiranjith
  20. Derek Vargas
  21. Sangeetha Mohan
  22. Sameer Phalke
  23. Boney Kuriakose
  24. Aju Antony
  25. Mart Ustav Jr
  26. Stephan C. Schuster
  27. Sachdev Sidhu
  28. Jagath R. Junutula
  29. Natalia Jura
  30. Somasekar Seshagiri

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Abstract

COVID-19 is a respiratory illness caused by a novel coronavirus called SARS-CoV-2. The viral spike (S) protein engages the human angiotensin-converting enzyme 2 (ACE2) receptor to invade host cells with ~10–15-fold higher affinity compared to SARS-CoV S-protein, making it highly infectious. Here, we assessed if ACE2 polymorphisms can alter host susceptibility to SARS-CoV-2 by affecting this interaction. We analyzed over 290,000 samples representing >400 population groups from public genomic datasets and identified multiple ACE2 protein-altering variants. Using reported structural data, we identified natural ACE2 variants that could potentially affect virus–host interaction and thereby alter host susceptibility. These include variants S19P, I21V, E23K, K26R, T27A, N64K, T92I, Q102P and H378R that were predicted to increase susceptibility, while variants K31R, N33I, H34R, E35K, E37K, D38V, Y50F, N51S, M62V, K68E, F72V, Y83H, G326E, G352V, D355N, Q388L and D509Y were predicted to be protective variants that show decreased binding to S-protein. Using biochemical assays, we confirmed that K31R and E37K had decreased affinity, and K26R and T92I variants showed increased affinity for S-protein when compared to wildtype ACE2. Consistent with this, soluble ACE2 K26R and T92I were more effective in blocking entry of S-protein pseudotyped virus suggesting that ACE2 variants can modulate susceptibility to SARS-CoV-2.

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  1. Version published to 10.1038/s42003-021-02030-3
  2. ScreenIT

    SciScore for 10.1101/2020.04.07.024752: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    RandomizationBecause Fst values vary based on variants used (Bhatia et al. 2013), we calculated the Fst in a set of randomly selected genes on the same chromosomes matched by the length decile to use for comparison.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableFst Analysis: To assess genetic variation in the coding region of ACE2, we calculated the fixation index (Fst) from 2,381 unrelated individuals across 26 populations in the 1000 Genomes Project Phase 3 and 57,783 female individuals across eight populations in gnomAD.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Fst Analysis: To assess genetic variation in the coding region of ACE2, we calculated the fixation index (Fst) from 2,381 unrelated individuals across 26 populations in the 1000 Genomes Project Phase 3 and 57,783 female individuals across eight populations in gnomAD.
    1000 Genomes Project
    suggested: (1000 Genomes Project and AWS, RRID:SCR_008801)
    Phylogenetic trees were constructed using the PhyML webserver (www.phylogeny.fr).
    PhyML
    suggested: (PhyML, RRID:SCR_014629)
    Structural Analysis: Each identified variant was mapped, modeled, and analyzed in Pymol using the recently deposited crystal structures 6VW1 and 6LZG of human ACE2 bound to either chimeric SARS CoV-2 RBD (6VW1) or complete SARS CoV-2 RBD (6LZG).
    Pymol
    suggested: (PyMOL, RRID:SCR_000305)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • No conflict of interest statement was detected. If there are no conflicts, we encourage authors to explicit state so.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2020.04.07.024752v1 on bioRxiv