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. Barbara E. Engelhardt
  30. James E. Peters
  31. Don D. Sin
  32. Stephen Burgess
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Abstract

Objectives

To use human genetic variants that proxy angiotensin-converting enzyme (ACE) inhibitor drug effects and cardiovascular risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 gene expression and circulating ACE2 levels.

Design

Two-sample Mendelian randomization (MR) analysis.

Setting

Summary-level genetic association data.

Participants

Participants were predominantly of European ancestry. Variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors (body mass index, chronic obstructive pulmonary disease, lifetime smoking index, low-density lipoprotein cholesterol, systolic blood pressure and type 2 diabetes mellitus) were selected from publicly available genome-wide association study data (sample sizes ranging from 188,577 to 898,130 participants). Genetic association estimates for lung expression of ACE2 and TMPRSS2 were obtained from the Gene-Tissue Expression (GTEx) project (515 participants) and the Lung eQTL Consortium (1,038 participants). Genetic association estimates for circulating plasma ACE2 levels were obtained from the INTERVAL study (4,947 participants).

Main outcomes and measures

Lung ACE2 and TMPRSS2 expression and plasma ACE2 levels.

Results

There were no association of genetically proxied ACE inhibition with any of the outcomes considered here. There was evidence of a positive association of genetic liability to type 2 diabetes mellitus with lung ACE2 gene expression in GTEx (p = 4×10−4) and with circulating plasma ACE2 levels in INTERVAL (p = 0.03), but not with lung ACE2 expression in the Lung eQTL Consortium study (p = 0.68). There were no associations between genetically predicted levels of the other cardiometabolic traits with the outcomes.

Conclusions

This study does not provide evidence to support that ACE inhibitor antihypertensive drugs affect lung ACE2 and TMPRSS2 expression or plasma ACE2 levels. In the current COVID-19 pandemic, our findings do not support a change in ACE inhibitor medication use without clinical justification.

Summary boxes

What is already known on this topic

  • Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current coronavirus disease 2019 (COVID-19) pandemic.

  • Serine protease TMPRSS2 is involved in priming the SARS-CoV-2 spike protein for cellular entry through the angiotensin-converting enzyme 2 (ACE2) receptor.

  • Expression of ACE2 and TMPRSS2 in the lung epithelium might have implications for risk of SARS-CoV-2 infection and severity of COVID-19.

What this study adds

  • We used human genetic variants that proxy ACE inhibitor drug effects and cardiometabolic risk factors to provide insight into how these exposures affect lung ACE2 and TMPRSS2 expression and circulating ACE2 levels.

  • Our findings do not support the hypothesis that ACE inhibitors have effects on ACE2 expression.

  • We found some support for an association of genetic liability to type 2 diabetes mellitus with higher lung ACE2 expression and plasma ACE2 levels, but evidence was inconsistent across studies.

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