Exploring Diseases/Traits and Blood Proteins Causally Related to Expression of ACE2, the Putative Receptor of SARS-CoV-2: A Mendelian Randomization Analysis Highlights Tentative Relevance of Diabetes-Related Traits

OBJECTIVE COVID-19 has become a major public health problem. There is good evidence that ACE2 is a receptor for SARS-CoV-2, and high expression ofACE2may increase susceptibility to infection. We aimed to explore risk factors affecting susceptibility to infection and prioritize drug repositioning candidates, based on Mendelian randomization (MR) studies onACE2lung expression. RESEARCH DESIGN AND METHODS We conducted a phenome-wide MR study to prioritize diseases/traits and blood proteins causally linked toACE2lung expression in GTEx. We also explored drug candidates whose targets overlapped with the top-ranked proteins in MR, as these drugs may alterACE2expression and may be clinically relevant. RESULTS The most consistent finding was tentative evidence of an association between diabetes-related traits and increasedACE2expression. Based on one of the largest genome-wide association studies on type 2 diabetes mellitus (T2DM) to date (N= 898,130), T2DM was causally linked to raisedACE2expression (P= 2.91E-03; MR-IVW). Significant associations (at nominal level;P< 0.05) withACE2expression were observed across multiple diabetes data sets and analytic methods for T1DM, T2DM, and related traits including early start of insulin. Other diseases/traits having nominal significant associations with increased expression included inflammatory bowel disease, (estrogen receptor-positive) breast cancer, lung cancer, asthma, smoking, and elevated alanine aminotransferase. We also identified drugs that may target the top-ranked proteins in MR, such as fostamatinib and zinc. CONCLUSIONS Our analysis suggested that diabetes and related traits may increaseACE2expression, which may influence susceptibility to infection (or more severe infection). However, none of these findings withstood rigorous multiple testing corrections (at false discovery rate <0.05). Proteome-wide MR analyses might help uncover mechanisms underlyingACE2expression and guide drug repositioning. Further studies are required to verify our findings.