Exploring Diseases/Traits and Blood Proteins Causally Related to Expression of ACE2, the Putative Receptor of SARS-CoV-2: A Mendelian Randomization Analysis Highlights Tentative Relevance of Diabetes-Related Traits

  1. Shitao Rao
  2. Alexandria Lau
  3. Hon-Cheong So

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

COVID-19 has become a major public health problem. There is good evidence that ACE2 is a receptor for SARS-CoV-2, and high expression of ACE2 may increase susceptibility to infection. We aimed to explore risk factors affecting susceptibility to infection and prioritize drug repositioning candidates, based on Mendelian randomization (MR) studies on ACE2 lung expression.

RESEARCH DESIGN AND METHODS

We conducted a phenome-wide MR study to prioritize diseases/traits and blood proteins causally linked to ACE2 lung expression in GTEx. We also explored drug candidates whose targets overlapped with the top-ranked proteins in MR, as these drugs may alter ACE2 expression and may be clinically relevant.

RESULTS

The most consistent finding was tentative evidence of an association between diabetes-related traits and increased ACE2 expression. Based on one of the largest genome-wide association studies on type 2 diabetes mellitus (T2DM) to date (N = 898,130), T2DM was causally linked to raised ACE2 expression (P = 2.91E−03; MR-IVW). Significant associations (at nominal level; P < 0.05) with ACE2 expression were observed across multiple diabetes data sets and analytic methods for T1DM, T2DM, and related traits including early start of insulin. Other diseases/traits having nominal significant associations with increased expression included inflammatory bowel disease, (estrogen receptor–positive) breast cancer, lung cancer, asthma, smoking, and elevated alanine aminotransferase. We also identified drugs that may target the top-ranked proteins in MR, such as fostamatinib and zinc.

CONCLUSIONS

Our analysis suggested that diabetes and related traits may increase ACE2 expression, which may influence susceptibility to infection (or more severe infection). However, none of these findings withstood rigorous multiple testing corrections (at false discovery rate <0.05). Proteome-wide MR analyses might help uncover mechanisms underlying ACE2 expression and guide drug repositioning. Further studies are required to verify our findings.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.03.04.20031237: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    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:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • 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.

  2. Version published to 10.2337/dc20-0643
  3. Version published to 10.1101/2020.03.04.20031237 on medRxiv