Affiliation:
1. Affiliated Hospital of Guangdong Medical University
2. Guangdong Medical University
3. University of North Texas Health Science Center
Abstract
Abstract
Background
Recent numerous epidemiology and clinical association studies reported that ApoE polymorphism may associate 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 spike protein and between ApoE and also the SARS-CoV-2 primary receptor ACE2. 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 carries genotypes VS non-ε4 carries 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 the spike protein and ACE2 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.
Publisher
Research Square Platform LLC