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

Dipender Gill, Marios Arvanitis, Paul Carter, Ana I Hernandez Cordero, Brian Jo, Ville Karhunen, Susanna C Larsson, Xuan Li, Sam M Lockhart, Amy M Mason, Evanthia Pashos, Ashis Saha, Vanessa Tan, Verena Zuber, Yohan Bosse, 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, Barbara E Engelhard, James E Peters, Don Sin, Stephen Burgess

April 2020

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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.

Type

Preprint

Publication

In medRxiv

Ashis Saha

Principal Scientific Researcher

My research interests include computational biology and machine learning.