COVID-19 enters the expanding network of apolipoprotein E4-related pathologies

Abstract

COVID-19 incidence and case fatality rates (CFR) differ among ethnicities, stimulating efforts to pinpoint genetic factors that could explain these phenomena. In this regard, the multiallelic apolipoprotein E (APOE) gene has recently been interrogated in the UK biobank cohort, demonstrating associations of the APOE ε4/ε4 genotype with COVID-19 severity and mortality. The frequency of the ε4 allele and thus the distribution of APOE ε4/ε4 genotype may differ among populations. We have assessed APOE genotypes in 1638 Greek individuals, based on haplotypes derived from SNP rs7412 and rs429358 and found reduced frequency of ε4/ε4 compared to the British cohort. Herein we discuss this finding in relation to CFR and hypothesize on the potential mechanisms linking APOE ε4/ε4 to severe COVID-19. We postulate that the metabolic deregulation ensued by APOE4, manifested by elevated cholesterol and oxidized lipoprotein levels, may be central to heightened pneumocyte susceptibility to infection and to exaggerated lung inflammation associated with the ε4/ε4 genotype. We also discuss putative dietary and pharmacological approaches for the prevention and management of COVID-19 in APOE ε4/ε4 individuals.

APOE4-mediated Alzheimer disease and “Vascular”—“Meningeal Lymphatic” components: towards a novel therapeutic era?

“…Furthermore, the notion that the brain can act as neurosecretory organ mediating immune responses, by which the APOE4-mediated drainage can play a regulatory role as opposed to a passive role, cannot be excluded [ 29 , 30 ]. Lastly, it would be intriguing to assess in future studies whether APOE4’s role on COVID-19 infection is mediated not only through neurotropic actions and behavioral aspects (e.g., people with APOE4 status AD are more prone to COVID-19 infection) [ 31 , 32 ] but also through vascular-meningeal lymphatic pathways (following initial observations in the peripheral system [ 33 ]).…”

OnTheFly2.0: a text-mining web application for automated biomedical entity recognition, document annotation, network and functional enrichment analysis

“…Cellular/extracellular components predicted to be associated with biomarkers of severe COVID-19 included extracellular space (GO:0005615, GO:0005576), plasma membrane (GO:0009897, GO:0009986, GO:0098552) and, interestingly, membrane microdomains (also called ‘membrane rafts’; GO:0098857, GO:0045121) ( Supplementary Table S7 ). The latter emerge as important cellular components implicated in (i) the initial binding of SARS-CoV-2 to ACE2 receptor, (ii) virus internalization and (iii) cell-to-cell transmission [reviewed in ( 61 )]. Pertinent to knowledge discovery, this biological information was extracted in the absence of specific reference to membrane microdomains in any of the six meta-analysis reports that were interrogated.…”

A Chinese host genetic study discovered type I interferons and causality of cholesterol levels and WBC counts on COVID-19 severity

“…When they are exposed to SARS-CoV-2, the accumulation of cholesterol in alveolar epithelial cells increased the density of lipid rafts, from which the virus binds to its target receptor ACE2. Therefore, higher density of lipid rafts facilitates the bindings in cell membranes and eventually raised the susceptibility to SARS-CoV-2 infection and severity of COVID-19 14,40,41 . The genetic mechanism is illustrated in Figure 4D.…”