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

Our study has a number of strengths. We used genetic variants as instrumental variables for studying the effect of ACEi drugs and cardiometabolic risk factors, and were therefore able to investigate their causal effects on ACE2 and TMPRSS2 expression in the lung, and ACE levels in the plasma (33) . For ACEi drugs effects, we used two complementary instrument selection strategies based on associations of variants at the ACE locus with circulating serum ACE levels and SBP respectively, and the consistent findings with both approaches add strength to our conclusions. Our Mendelian randomization approach is better able to overcome the confounding and reverse causation bias that can limit causal inferences from conventional epidemiological approaches (30, 62) . Considering independent cohorts to assess lung expression of ACE2 and TMPRSS2 (39, 40) , and plasma levels of ACE2 (43), we were able to explore consistency in our results and our conclusions are therefore less vulnerable to false positive findings.