The Impact of ACE2 Polymorphisms on COVID-19 Disease: Susceptibility, Severity, and Therapy

Abstract

The coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has currently spread worldwide, leading to high morbidity and mortality. As the putative receptor of SARS-CoV-2, angiotensin-converting enzyme 2 (ACE2) is widely distributed in various tissues and organs of the human body. Simultaneously, ACE2 acts as the physiological counterbalance of ACE providing homeostatic regulation of circulating angiotensin II levels. Given that some ACE2 variants are known to cause an increase in the ligand-receptor affinity, their roles in acquisition, progression and severity of COVID-19 disease have aroused widespread concerns. Therefore, we summarized the latest literature and explored how ACE2 variants and epigenetic factors influence an individual’s susceptibility to SARS-CoV-2 infection and disease outcome in aspects of ethnicity, gender and age. Meanwhile, the possible mechanisms for these phenomena were discussed. Notably, recombinant human ACE2 and ACE2-derived peptides may have special benefits for combating SARS-CoV-2 variants and further studies are warranted to confirm their effects in later stages of the disease process. As the uncertainty regarding the severity and transmissibility of disease rises, a more in-depth understanding of the host genetics and functional characteristics of ACE2 variants will not only help explain individual clinical differences of the disease, but also contribute to providing effective measures to develop solutions and manage future outbreaks of SARS-CoV-2.

Dying From COVID-19 or With COVID-19: A Definitive Answer Through a Retrospective Analysis of Mortality in Italy

“…Specifically, excluding internal causes gives further strength to the theories that identify COVID-19 as the principal cause of such a tragic scenario. COVID-19 dangerousness is confirmed at the molecular-genetic level [24]: compared to its predecessor, SARS-CoV-2 binds to the ACE2 peptidase domain two-four times more strongly, which increases its severity [25][26][27]. Besides, our results statistically support the greater virulence and mortality of COVID-19 in northern Italy and towards the male population [28][29][30].…”

Differences between Omicron SARS-CoV-2 RBD and other variants in their ability to interact with cell receptors and monoclonal antibodies

“…REGN-COV2 provided benefits in trials with rhesus macaques and golden hamsters, simulating mild and severe disease, respectively, enhancing viral clearance, and was released by some national health agencies for emergency use, such as Anvisa, the Brazilian agency (Baum et al, 2020; Weinreich et al, 2021). LY-CoV555, another promising neutralizing antibody that entered clinical evaluation, was also studied in a cocktail form with LY-CoV016 (P. Chen et al, 2021; Renn et al, 2020; Starr et al, 2021).…”

“…Here, we extended our previous in silico study (Giron et al, 2020) to investigate and compare the impact of these mutations on the interaction between the RBD and the human ACE2 since this is the very first step for the SARS-CoV-2 cellular entry. ACE2 polymorphisms were also included in our analysis as they were suggested to be a genetic factor that could affect the viral entry independently, but also the severity of the disease due to its role in comorbidities, such as hypertension (F. Chen et al, 2021; Möhlendick et al, 2021).…”

Characterization of ACE2 naturally occurring missense variants: impact on subcellular localization and trafficking

“…Moreover, the coordinates of ACE2 crystal structure were obtained from the protein data bank (PDB), PDB ID 6M17, excluding the coordinates of receptor binding domain (RBD) of SARS-CoV2 from the co-complexed B o AT1 dimer. I-TASSER was used to model the missing C terminal residues (769 to 805) and N terminal residues (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) of the ACE2 transmembrane helices (25). SWISS-MODEL was used to generate the three-dimensional homology models of mutant proteins using modeled full-length structure of ACE2 as a template (26).…”

“…By the beginning of the spread of COVID-19 infection in 2019, Cao et al and other groups have demonstrated that ACE2 expression levels and genetic variation may in uence its interaction with the SARS-CoV-2 spike S-protein (8,12,13). Therefore, the highlighted variable outcomes may explain some of the interindividual variability of the infection onset, susceptibility, and severity (9).…”