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

Emerging evidence suggests that patients with underlying cardiometabolic risk factors and airway disease are more likely to suffer with severe COVID-19 (7) (8) (9) (10) (11) (12) . It has been speculated that the angiotensin-converting enzyme inhibitor (ACEi) and angiotensin receptor blocker (ARB) classes of antihypertensive medication that are more commonly prescribed in patients with cardiometabolic risk factors might affect expression of ACE2, and thus affect susceptibility to SARS-CoV-2 infection and severity of consequent COVID-19 (15) (16) (17) (18) (19) (20) (21) . Although ACE and ACE2 are both dipeptidyl carboxydipeptidases, they have distinct physiological effects. ACE cleaves angiotensin I to angiotensin II, which consequently activates the angiotensin II receptor type 1 pathway resulting in vasoconstriction and inflammation. In contrast, ACE2 degrades angiotensin II to angiotensin 1-7 and angiotensin I to angiotensin 1-9. Angiotensin 1-9 activates the Mas receptor to have vasodilatory and anti-inflammatory effects. Animal studies have supported effects of ACEi and ARB drugs on ACE2 expression and activity (22) (23) (24) (25) (26) (27) (28) (29) , with mixed findings for associations of ACEi and ARB drug use with ACE2 activity and levels in human tissues also reported (30) (31) (32) . It is important that any causal effects of these medications and cardiometabolic traits on ACE2 expression be further investigated.