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 Mendelian randomization approach uses genetic variants related to an exposure as instrumental variables for investigating the effect of that exposure on an outcome (33) . Genetic variants are treated analogously to treatment allocation in a randomized controlled trial. Typically, molecular measurements such as gene expression or circulating protein levels are regarded in Mendelian randomization investigations as exposure variables. Here, following the work of Rao, Lau and So (34), we treat these molecular measurements as the outcomes in our investigation. The aim of this study was to apply Mendelian randomization to investigate whether ACE2 and TMPRSS2 gene expression in the lung and circulating levels of ACE2 in the plasma are associated with 1) genetic variants in the ACE gene region that can be considered as proxies for the effect of ACEi drugs, and 2) genetic variants related to cardiometabolic risk factors.