Systematic identification of ACE2 expression modulators reveals cardiomyopathy as a risk factor for mortality in COVID-19 patients

  1. Navchetan Kaur
  2. Boris Oskotsky
  3. Atul J. Butte
  4. Zicheng Hu

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Abstract

Background

Angiotensin-converting enzyme 2 (ACE2) is the cell-entry receptor for SARS-CoV-2. It plays critical roles in both the transmission and the pathogenesis of COVID-19. Comprehensive profiling of ACE2 expression patterns could reveal risk factors of severe COVID-19 illness. While the expression of ACE2 in healthy human tissues has been well characterized, it is not known which diseases and drugs might be associated with ACE2 expression.

Results

We develop GENEVA (GENe Expression Variance Analysis), a semi-automated framework for exploring massive amounts of RNA-seq datasets. We apply GENEVA to 286,650 publicly available RNA-seq samples to identify any previously studied experimental conditions that could be directly or indirectly associated with ACE2 expression. We identify multiple drugs, genetic perturbations, and diseases that are associated with the expression of ACE2, including cardiomyopathy, HNF1A overexpression, and drug treatments with RAD140 and itraconazole. Our joint analysis of seven datasets confirms ACE2 upregulation in all cardiomyopathy categories. Using electronic health records data from 3936 COVID-19 patients, we demonstrate that patients with pre-existing cardiomyopathy have an increased mortality risk than age-matched patients with other cardiovascular conditions. GENEVA is applicable to any genes of interest and is freely accessible at http://genevatool.org .

Conclusions

This study identifies multiple diseases and drugs that are associated with the expression of ACE2. The effect of these conditions should be carefully studied in COVID-19 patients. In particular, our analysis identifies cardiomyopathy patients as a high-risk group, with increased ACE2 expression in the heart and increased mortality after SARS-COV-2 infection.

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  1. Version published to 10.1186/s13059-021-02589-4
  2. ScreenIT

    SciScore for 10.1101/2020.10.20.20216150: (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
    Data preparation: We downloaded the uniformly processed RNA-seq data from ARCHS4 website (https://amp.pharm.mssm.edu/archs4/download.html) on August 03, 2020.
    ARCHS4
    suggested: (ARCHS4, RRID:SCR_015683)
    We used the signature to query the Gene Ontology Biological Process database44.
    Ontology Biological Process
    suggested: None
    It is implemented in python web framework Django.
    python
    suggested: (IPython, RRID:SCR_001658)

    Results from OddPub: Thank you for sharing your code.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    When interpreting these findings, readers should take into account several limitations of our study. First, many of the ACE2 modulating conditions are discovered based on data from one study with small sample sizes. These results should be viewed as data-driven hypotheses rather than definitive proofs. Additional data is required to confirm the findings. Second, our analysis does not establish a direct link between COVID-19 risk and the identified ACE2 modulators. Clinical studies are required to test if these ACE2 modulating conditions alter the risk of COVID-19 infection and pathogenesis. Finally, the datasets profile the ACE2 expression in bulk tissues. Therefore, it is not clear if the variation of ACE2 expression is due to a change in cellular composition or a change in transcriptional regulation. Single-cell analysis is required to identify the cause of ACE2 expression change. Heart diseases are associated with severe COVID-19 illness through two mechanisms. Pre-existing heart conditions are comorbidities of COVID1928,40. On the other hand, SARS-COV-2 infection can induce acute myocardial injury30. Cardiomyopathy is one of the most common heart diseases. Compared to other age-related heart conditions, cardiomyopathy can affect individuals at any age. However, clinical studies were lacking to specifically characterize the disease severity of COVID-19 in patients with cardiomyopathy. Our transcriptional analysis highlights the significantly increased ACE2 expression in th...

    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.

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  3. Version published to 10.1101/2020.10.20.20216150v1 on medRxiv