ACE inhibition and cardiometabolic risk factors, lung ACE2 and TMPRSS2 gene expression, and plasma ACE2 levels: a Mendelian randomization study

  1. Dipender Gill
  2. Marios Arvanitis
  3. Paul Carter
  4. Ana I. Hernández Cordero
  5. Brian Jo
  6. Ville Karhunen
  7. Susanna C. Larsson
  8. Xuan Li
  9. Sam M. Lockhart
  10. Amy Mason
  11. Evanthia Pashos
  12. Ashis Saha
  13. Vanessa Y. Tan
  14. Verena Zuber
  15. Yohan Bossé
  16. Sarah Fahle
  17. Ke Hao
  18. Tao Jiang
  19. Philippe Joubert
  20. Alan C. Lunt
  21. Willem Hendrik Ouwehand
  22. David J. Roberts
  23. Wim Timens
  24. Maarten van den Berge
  25. Nicholas A. Watkins
  26. Alexis Battle
  27. Adam S. Butterworth
  28. John Danesh
  29. Emanuele Di Angelantonio
  30. Barbara E. Engelhardt
  31. James E. Peters
  32. Don D. Sin
  33. Stephen Burgess

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Abstract

Angiotensin-converting enzyme 2 (ACE2) and serine protease TMPRSS2 have been implicated in cell entry for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus responsible for coronavirus disease 2019 (COVID-19). The expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for the risk of SARS-CoV-2 infection and severity of COVID-19. We use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to investigate whether these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels. We observed no consistent evidence of an association of genetically predicted serum ACE levels with any of our outcomes. There was weak evidence for an association of genetically predicted serum ACE levels with ACE2 gene expression in the Lung eQTL Consortium ( p = 0.014), but this finding did not replicate. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in the Gene-Tissue Expression (GTEx) study ( p = 4 × 10 −4 ) and with circulating plasma ACE2 levels in the INTERVAL study ( p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study ( p = 0.68). There were no associations of genetically proxied liability to the other cardiometabolic traits with any outcome. This study does not provide consistent evidence to support an effect of serum ACE levels (as a proxy for ACE inhibitors) or cardiometabolic risk factors on lung ACE2 and TMPRSS2 expression or plasma ACE2 levels.

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  1. Version published to 10.1098/rsos.200958
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    SciScore for 10.1101/2020.04.10.20059121: (What is this?)

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    Table 1: Rigor

    NIH rigor criteria are not applicable to paper type.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    For each gene, expression values between samples were normalized using the trimmed means of M-values method in EdgeR (42).
    EdgeR
    suggested: (edgeR, RRID:SCR_012802)

    Results from OddPub: Thank you for sharing your data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our study also has limitations. We only investigated ACE2 and TMPRSS2 expression in the lung and circulating levels of ACE2 in the plasma, and it may be that expression in other tissues is more relevant to risk and severity of COVID-19. Similarly, cellular ACE2 may have very different biological effects to circulating plasma ACE2. The GWAS analyses for lung ACE2 expression and plasma ACE2 levels were all performed according to different protocols (39, 40, 43), and may therefore not be directly comparable. There was no available genetic instrument for the ARB antihypertensive drug class (36), and so we were not able to investigate this. The precision of our analyses was also limited, most notably for the lifetime smoking index results, which had widest confidence intervals. It may therefore be that our study was not sufficiently powered to exclude a clinically relevant effect for some exposures. The genetic variants that we used as instrumental variables may have pleiotropic effects where they affect the outcome through pathways independent of the exposure that they are proxying, and so bias the consequent Mendelian randomization estimates. While it is not possible to exclude this possibility, the relatively low heterogeneity detected between Mendelian randomization estimates produced by different variants, along with the consistency observed when performing analysis methods that are more robust to pleiotropy, suggests that this is unlikely to be a major source of bias (47). I...

    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 10.1101/2020.04.10.20059121v1 on medRxiv