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 also has limitations. We only investigated ACE2 and TMPRSS2 expression in the lung and circulating levels of ACE2 in the plasma, and it may be that expression in other tissues is more relevant to risk and severity of COVID-19. Similarly, cellular ACE2 may have very different biological effects to circulating plasma ACE2. The GWAS analyses for lung ACE2 expression and plasma ACE2 levels were all performed according to different protocols (39, 40, 43) , and may therefore not be directly comparable. There was no available genetic instrument for the ARB antihypertensive drug class (36) , and so we were not able to investigate this. The precision of our analyses was also limited, most notably for the lifetime smoking index results, which had widest confidence intervals. It may therefore be that our study was not sufficiently powered to exclude a clinically relevant effect for some exposures. The genetic variants that we used as instrumental variables may have pleiotropic effects where they affect the outcome through pathways independent of the exposure that they are proxying, and so bias the consequent Mendelian randomization estimates. While it is not possible to exclude this possibility, the relatively low heterogeneity detected between Mendelian randomization estimates produced by different variants, along with the consistency observed when performing analysis methods that are more robust to pleiotropy, suggests that this is unlikely to be a major source of bias (47) .