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

We did not find an association of genetically proxied ACE inhibition with lung ACE2 and TMPRSS2 expression or with circulating plasma levels of ACE2. These results therefore do not provide evidence to support that ACEi antihypertensive drugs affect risk or severity of COVID-19 through effects on ACE2 expression, as previously hypothesised (15) (16) (17) (18) (19) (20) (21) . Previously identified changes in ACE2 expression in human tissues following ACEi treatment may not be applicable to the lung or circulating plasma levels (30, 31) . Our findings support the stance of professional bodies for supporting continuation of ACEi and ARB antihypertensive drugs in patients with COVID-19 unless there is a clinical justification for stopping (52, 53) . Indeed, appropriate use of these medications is of proven benefit (54, 55) , and their abrupt interruption can also do considerable harm (56, 57) . While there has also been speculation that ACEi and ARB antihypertensive drugs might reduce severity of COVID-19 (20, (58) (59) (60) , with clinical trials to explore this currently planned (52), our findings are also consistent with guidance that patients should not start taking these drug classes unless clinically indicated (52) .