ApoE4 associated with severe COVID-19 outcomes via downregulation of ACE2 and imbalanced RAS pathway

Abstract

Background Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism might be associated with the risk and severity of coronavirus disease 2019 (COVID-19), and yielded inconsistent results. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection relies on its spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptor expressed on host cell membranes. Methods A meta-analysis was conducted to clarify the association between ApoE polymorphism and the risk and severity of COVID-19. Multiple protein interaction assays were utilized to investigate the potential molecular link between ApoE and the SARS-CoV-2 primary receptor ACE2, ApoE and spike protein. Immunoblotting and immunofluorescence staining methods were used to access the regulatory effect of different ApoE isoform on ACE2 protein expression. Results ApoE gene polymorphism (ε4 carrier genotypes VS non-ε4 carrier genotypes) is associated with the increased risk (P = 0.0003, OR = 1.44, 95% CI 1.18–1.76) and progression (P < 0.00001, OR = 1.85, 95% CI 1.50–2.28) of COVID-19. ApoE interacts with both ACE2 and the spike protein but did not show isoform-dependent binding effects. ApoE4 significantly downregulates ACE2 protein expression in vitro and in vivo and subsequently decreases the conversion of Ang II to Ang 1–7. Conclusions ApoE4 increases SARS-CoV-2 infectivity in a manner that may not depend on differential interactions with the spike protein or ACE2. Instead, ApoE4 downregulates ACE2 protein expression and subsequently the dysregulation of renin–angiotensin system (RAS) may provide explanation by which ApoE4 exacerbates COVID-19 disease.

Sister haplotypes and recombination disequilibrium: a new approach to identify associations of haplotypes with complex diseases

“…For example, M1M3M4* haplotype containing risk factor apoE-ε4 and M1M3M6 haplotype containing risk factor apoE-ε3 were found to be associated with risk for AD in small human population (210 AD cases and 159 non-demented elderly controls) using our sister haplotypes and RD test. ApoE-ε3 ( Huang et al, 1995 ; DeMattos et al, 2001 ; Hopkins et al, 2002 ; Sen et al, 2012 ; Pedachenko et al, 2015 ; Mahan et al, 2022 ; Sepulveda-Falla et al, 2022 ; Mulgrave et al, 2023 ) and apoE-ε4 ( Ayyubova, 2023 ; Chen et al, 2023 ; Hamza et al, 2023 ; Koutsodendris et al, 2023 ; Pires and Rego, 2023 ; Sun and Xie, 2023 ; Zhou et al, 2023 ) have been verified to be risk factors for AD. Fallin et al (2001) however found that 3 haplotypes in configure 2 flanking M3 and M4 were significantly associated with risk for AD by using individual-others pairs.…”

Blood ACE2 Protein Level Correlates with COVID-19 Severity

“…RAS operates via the classic ACE/Angiotensin (Ang) II/Ang II type 1(AT1) receptor axis and the non-classical ACE2/Ang 1–7/Mas receptor (MasR) axis. The classical pathway is associated with the impairment of respiratory conditions, while non-classical plays a protective role in COVID-19 complications as ARDS [ 20 , 29 ]. ACE2 as a carboxypeptidase converts the decapeptide angiotensin I (AngI) to Ang (1–9) and the octapeptide Ang II to Ang (1–7) [ 30 ].…”

Apolipoprotein E and viral infection: Risks and Mechanisms

“…However, using a biolayer interferometry binding assay, a recent study found that ApoE interacts with the RBD of the spike protein in an isoform-independent manner. 56 However, whether the interactions could affect the affinity between ACE2 and the spike protein and subsequently SARS-CoV-2 infection is unknown. In contrast, an in vitro study reported an inhibiting effect of ApoE on SARS-CoV-2 infection.…”

“…ApoE4 has been reported to be associated with significant inhibition of ACE2 expression, 67 which may also be one of the reasons for the severity of COVID-19 caused by ApoE4. 56 The increased risk of COVID-19 infection with ApoE4 may partly explain why Black Africans suffer a higher possibility of COVID-19 severity and mortality; the prevalence of the ε4 / ε4 allele is more common in black African individuals (population frequency, 30%–40%) than in Caucasian and Asian individuals (population frequency, 7%–20% and 5%–15%, respectively). 68 , 69 …”