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

The novel coronavirus 2019-nCoV has caused major outbreaks in many parts of the world. A better understanding of the pathophysiology of COVID-19 is urgently needed. Clinically, it is important to identify who may be susceptible to infection and identify treatments for the disease.There is good evidence that ACE2 is a receptor for 2019-nCoV, and studies also suggested that high expression of ACE2 may increase susceptibility to infection. Here we conducted a phenome-wide Mendelian randomization (MR) study to prioritize diseases/traits and blood proteins that may be causally linked to ACE2 expression in the lung. Expression data was based on GTEx. We also explored drug candidates whose targets overlapped with the top-ranked proteins in MR analysis, as these drugs could potentially alter ACE2 expression and may be clinically relevant. Notably, MR is much less vulnerable to confounding and reverse causality compared to observational studies.The most consistent finding was a tentative causal association between diabetes-related traits and increased ACE2 expression. Based on one of the largest GWAS on type II diabetes (T2DM) to date (N=898,130), we found that T2DM is causally linked to raised ACE2 expression (beta=0.1835, 95% CI 0.0853-0.2817; p=2.49E-4; GSMR method). Significant associations (at nominal level; p<0.05) was also observed across multiple datasets, with different analytic methods, and for both type I and II diabetes. Other diseases/traits having nominal significant associations with increased ACE2 included inflammatory bowel disease, (ER+) breast and lung cancers, asthma, smoking and elevated ALT, among others. We also uncovered a number of plasma/serum proteins potentially linked to altered ACE2 expression, and the top enriched pathways included cytokine-cytokine-receptor interaction, VEGF signaling, JAK-STAT signaling etc. We also explored drugs that target some of the top-ranked proteins in the MR analysis.

Predicting mortality due to SARS-CoV-2: A mechanistic score relating obesity and diabetes to COVID-19 outcomes in Mexico

“…The relationship between increased risk of mortality attributable to acute severe respiratory infections in patients with diabetes mellitus has been extensively reported, particularly for the Italy [5,23,24]. Increased susceptibility for COVID-19 in patients with diabetes may be explained for several potential mechanisms including an increased lung ACE2 expression and elevated circulating levels of furin, a protease involved in viral entry to cells, and a decreased clearance of SARS-CoV-2 viral particles in subjects with diabetes and/or hypertension associated with ACE2 expression [25][26][27][28]. Impairments in immunity observed in patients with diabetes are characterized by initial delay in activation of Th1 cell-mediated immunity and late hyper-inflammatory response and are consistent with the increased risk associated with additional immunosuppression observed with our data [29].…”

Exploring the Demographics and Clinical Characteristics Related to the Expression of Angiotensin-Converting Enzyme 2, a Receptor of SARS-CoV-2

“…Our results suggested that smokers, especially males, may be more susceptible to infection with COVID-19. With regard to the association between cancer and susceptibility to infection with COVID-19, it has been reported in recent studies that breast, colorectal, and lung cancer may be associated with an increased expression of ACE2 (8,10). Zheng et al (16) reported that 8 (1%) of 1,590 COVID-19 cases had a history of cancer, which seems to be higher than the incidence of cancer in the overall Chinese population ([0.29%] per 100,000 people).…”

“…For example, Liu et al (5) reported that older age (odds ratio [OR] = 8.546, 95% confidence interval [CI] = 1.628-44.864, p = 0.011) and smoking (OR = 14.285, 95% CI = 1.577-25.000, p = 0.018) are risk factors for the progression of COVID-19. Rao et al (8) showed that over 25% of patients with COVID-19 have a history of hypertension (12.9%) and diabetes (5.4%). However, it is still unclear whether the above factors, or perhaps even other factors, are associated with susceptibility to COVID- 19.…”

“…Several studies have investigated the relationship between the expression level of ACE2 and the demographic or clinical characteristics of COVID-19. For example, Rao et al performed a phenome-wide Mendelian randomization study and found that type II diabetes is causally linked to an increased expression of ACE2 (8). Chen et al (10) showed that ACE2 is mainly expressed in the epithelial cells of the colon and that its expression is increased the most in patients with colorectal cancer followed by patients with adenoma, compared to healthy controls.…”

SARS-CoV-2 receptor networks in diabetic and COVID-19 associated kidney disease

“…ACE2 gene expression studies of kidney tissue to date have been inconclusive concerning regulation in kidney disease [50][51][52][53] . A strength of our study is the definition of the ACE2 expression to the cellular context of PTEC in distinct infectious and non-infectious kidney diseases.…”