ACE2 polymorphisms and individual susceptibility to SARS-CoV-2 infection: insights from an in silico study

  1. Matteo Calcagnile
  2. Patricia Forgez
  3. Antonio Iannelli
  4. Cecilia Bucci
  5. Marco Alifano
  6. Pietro Alifano

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Abstract

The current SARS covid-19 epidemic spread appears to be influenced by ethnical, geographical and sex-related factors that may involve genetic susceptibility to diseases. Similar to SARS-CoV, SARS-CoV-2 exploits angiotensin-converting enzyme 2 (ACE2) as a receptor to invade cells, notably type II alveolar epithelial cells. Importantly, ACE2 gene is highly polymorphic. Here we have used in silico tools to analyze the possible impact of ACE2 single-nucleotide polymorphisms (SNPs) on the interaction with SARS-CoV-2 spike glycoprotein. We found that S19P (common in African people) and K26R (common in European people) were, among the most diffused SNPs worldwide, the only two SNPs that were able to potentially affect the interaction of ACE2 with SARS-CoV-2 spike. FireDock simulations demonstrated that while S19P may decrease, K26R might increase the ACE2 affinity for SARS-CoV-2 Spike. This finding suggests that the S19P may genetically protect, and K26R may predispose to more severe SARS-CoV-2 disease.

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  1. ScreenIT

    SciScore for 10.1101/2020.04.23.057042: (What is this?)

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

    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Binding interface characterization: The selected PDB models were analyzed by a structural point of view using Chimera software in order to identify the glycosylation sites and the secondary structures of proteins involved in the binding between ACE2 and Spike protein receptor binding domain (RBD).
    Chimera
    suggested: (Chimera, RRID:SCR_002959)

    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: We detected the following sentences addressing limitations in the study:
    Although with limitations and caveats of in silico technology, this study addresses the question of whether some ACE2 SNPs may be associated with a different individual susceptibility to COVID-19. To alleviate these limitations, we used a combination of bioinformatics tools, and tested different crystallographic models. Four months after the spread of the SARS COVID-19, its worldwide distribution remains extremely uneven. Lethality is even more inhomogeneous among and within countries, with figures of 12.6% in Italy43, and 0.6% in South Korea44. Although differences in mortality might have various causes, including access and efficiency of health systems, total number of people tested, presence and severity of symptoms in tested populations, they are so impressive that it seems legitimate to search for other factors possibly related to individuals as the elements of a population. Ultimately, infectivity and lethality do not seem linearly related, and probably represent problems to be solved with different, albeit complementary, approaches. Basic aspects of epidemiology of the disease warrant some considerations: differently from other countries, in South Korea (which adopted a policy of extensive PCR screening), women represent 63% of infected people44 as opposed to 50% in Italy43 (where the policy has been to test only severely symptomatic cases for a long time). Lethality figures in women were 0.4% and 8.7% in South Korea and Italy, respectively, as opposed to 1% and 16.4% ...

    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:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • No funding statement was detected.
    • No protocol registration statement was detected.

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  2. Version published to 10.1101/2020.04.23.057042v1 on bioRxiv