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

The main inverse-variance weighted method Mendelian randomization results for the cardiometabolic risk factors are displayed in Figure 2 for lung ACE2 expression and plasma ACE2 concentrations, and in Figure 3 for lung TMPRSS2 expression. There was evidence of a positive association of genetic liability to T2DM with lung ACE2 gene expression in GTEx (p = 4x10 -4 ), and with circulating plasma ACE2 levels in INTERVAL (p = 0.03) (Supplementary Figure 1) . Similar point estimates were obtained when performing the weighted median, MR-Egger and contaminationmixture Mendelian randomization sensitivity analyses that are more robust to the presence of pleiotropic variants, although the confidence intervals were wider (Supplementary Table 9 ). The MR-Egger method did not identify any evidence of directional pleiotropy biasing the analysis (Supplementary Table 9 ). There was no evidence of an association of genetic liability to T2DM with lung ACE2 gene expression in the Lung eQTL Consortium (p = 0.68). There was no evidence of an association between genetically predicted levels of any of the other cardiometabolic traits with ACE2 or TMPRSS2 gene expression in GTEx or the Lung eQTL Consortium, or with circulating plasma ACE2 levels in INTERVAL.