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

Abstract

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 of ACE2 may 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 on ACE2 lung expression. RESEARCH DESIGN AND METHODSWe conducted a phenome-wide MR study to prioritize diseases/traits and blood proteins causally linked to ACE2 lung expression in GTEx. We also explored drug candidates whose targets overlapped with the top-ranked proteins in MR, as these drugs may alter ACE2 expression and may be clinically relevant. RESULTSThe most consistent finding was tentative evidence of an association between diabetes-related traits and increased ACE2 expression. Based on one of the largest genome-wide association studies on type 2 diabetes mellitus (T2DM) to date (N 5 898,130), T2DM was causally linked to raised ACE2 expression (P 5 2.91E203; MR-IVW). Significant associations (at nominal level; P < 0.05) with ACE2 expression 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. CONCLUSIONSOur analysis suggested that diabetes and related traits may increase ACE2 expression, 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 underlying ACE2 expression and guide drug repositioning. Further studies are required to verify our findings.

Impact of Corona Virus Disease-19 (COVID-19) pandemic on gastrointestinal disorders

“…The pathogenicity of COVID-19 agent in relation to the GI tract has been recently reviewed elsewhere [22]. Briefly, an S protein component of the virus interacts with cell surface angiotensin-converting enzyme type 2 (ACE-2) receptors to enter human host cells [23]. The ACE-2 receptors are expressed abundantly in the nasal epithelium and upper and lower respiratory tract epithelial cells [3].…”

Encountering COVID-19 as Endocrinologists

“…First, expression levels of ACE2, the cellular receptor of SARS-CoV-2, are known to be increased in the lung, kidney, heart, and pancreas in rodent models of diabetes [56,57]. In a genome-wide Mendelian randomization study, diabetes was causally associated with increased lung ACE2 expression [58]. These studies support the hypothesis that patients with diabetes are especially susceptible to SARS-CoV-2 infection.…”

“A Chain Only as Strong as Its Weakest Link”: An Up-to-Date Literature Review on the Bidirectional Interaction of Pulmonary Fibrosis and COVID-19

“… 119 Additionally, a proteome-wide mendelian randomization analysis identified proteins inhibited by nintedanib that are causally linked to elevated ACE2. 120 This result might also imply a possible contribution of nintedanib on lowering ACE2 expression, thus mediating a decreased susceptibility to SARS-CoV-2 infection.…”