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

Author(s): Gill, Dipender; Arvanitis, Marios; Carter, Paul; Hernández Cordero, Ana I; Jo, Brian; et al

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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.
Publication Date: 2020
Citation: Gill, Dipender, Marios Arvanitis, Paul Carter, Ana I. Hernández Cordero, Brian Jo, Ville Karhunen, Susanna C. Larsson, Xuan Li, Sam M. Lockhart, Amy Mason, Evanthia Pashos, Ashis Saha, Vanessa Y. Tan, Verena Zuber, Yohan Bossé, Sarah Fahle, Ke Hao, Tao Jiang, Philippe Joubert, Alan C. Lunt, Willem Hendrik Ouwehand, David J. Roberts, Wim Timens, Maarten van den Berge, Nicholas A. Watkins, Alexis Battle, Adam S. Butterworth, John Danesh, Emanuele Di Angelantonio, Barbara E. Engelhardt, James E. Peters, Don D. Sin and Stephen Burgess. “ACE Inhibition and Cardiometabolic Risk Factors, Lung ACE2 and TMPRSS2 Gene Expression, and Plasma ACE2 Levels: A Mendelian Randomization Study.” Royal Society Open Science 7 (11) (2020): 200958. doi:10.1098/rsos.200958
DOI: 10.1098/rsos.200958
EISSN: 2054-5703
Pages: 200958
Language: eng
Type of Material: Journal Article
Journal/Proceeding Title: Royal Society Open Science
Version: Final published version. This is an open access article.

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