Variations in human ACE2 genetics associated with coronavirus susceptibility

The variabilities found in patients infected with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from different regions and ethnicities have led scientists to investigate the role of human genetic variation in determining disease severity of the coronavirus disease 2019 (COVID-19). To this end, several genome-related studies have revealed the important associations that exist between SARS-CoV-2 infection and host genes.

Study: Susceptibilities of human ACE2 genetic variants in coronavirus infection. Image Credit: Kateryna Kon /

Genetic variations in ACE2

SARS-CoV-2, as well as several other coronaviruses including SARS-CoV and the human coronavirus NL63 (HCoV-NL63) utilize the angiotensin-converting enzyme 2 (ACE2) receptor to gain entry into host cells. On the surface of these viruses sits the viral spike (S) protein, which consists of S1 and S2 domains. The S1 domain primarily interacts with ACE2 through its receptor-binding domain (RBD) to allow for S2-mediated fusion of the virus to the host cell.

To date, several studies have identified numerous variations in the ACE2 gene that have been associated with arterial hypertension, diabetes mellitus, cerebral stroke, coronary artery disease, heart septal wall thickness, and ventricular hypertrophy. ACE2 also acts as a vasodilator and exerts critical modulatory effects on the cardiovascular system.

While ACE2 is the receptor for SARS-CoV, SARS-CoV-2, and HCoV-NL63, it is also the major genetic determinant of host range and tissue tropism for these viruses. However, any association between these ACE2 gene variations and their binding with the SARS-CoV-2 and subsequent susceptibility of SARS-CoV-2 infection is unknown.

In a recent study published on the preprint server bioRxiv,* the researchers sought to understand the genetic variability in ACE2 that may contribute to inconsistent clinical outcomes of COVID-19. More specifically, the authors investigated single-nucleotide polymorphisms (SNPs) in the coding region of the ACE2 gene.

Study findings

The researchers performed a series of biochemical and functional experiments to evaluate the impact of ACE2 SNPs on the interaction between viral S proteins and their entry into cells in both in vitro and in vivo models.

Upon identification of previously reported ACE2 single-nucleotide variants (SNVs) that result in missense mutations, the researchers chose 12 ACE2 SNVs associated with amino acid substitutions at or near the interface of SARS-CoV-2, SARS-CoV-, and HCoV-NL63 S proteins. Of these SNVs, 4 were found to have a mutated residue located at the interface with the SARS-CoV-2 or SARS-CoV S protein, 537K, M82I, and D355N, as well as 2 at the interface of the S protein and D355N of HCoV-NL-63.

The binding affinity of these ACE2 variants was assessed through a computational platform. This experiment found that while most of the ACE2 SNVs did not exhibit any differences in their interaction with the viral S proteins, the SNVs E37K, G352V, and D355N showed significantly reduced binding with certain S proteins.

Further analysis through flow cytometry confirmed the different binding abilities of the ACE2 variants to the S proteins of SARS-CoV-2, SARS-CoV, and HCoV-NL63. In particular, the D355N variant was found to be significantly impaired among all threew viral S proteins. In fact, this variant had a significant increase in predicted binding free energy, limited binding affinity with S proteins in both cell-based and surface plasmon resonance (SPR) assays, as well as reduced susceptibility to authentic SARS-CoV-2 infection in both in vitro and in vivo models.

“Based on analysis of the structure of ACE2 complexed with SARS-CoV-2 RBD, the loop in a beta-sheet (K353-R357) of ACE2 is critical for RBD binding, and the D355N mutation could disrupt the beta-sheet structure, which might explain why D355N mutant is refractory to binding by the SARS-CoV-2 spike protein.”

Future outlook

The identification of genetic factors that determine the clinical outcome of SARS-CoV-2 infection are both biologically and medically significant for understanding the pathogenesis of COVID-19, as well as supporting the development of adequate countermeasures. To this end, the findings of the current study provide an insight into how ACE2 SNVs interact with the S proteins of various HCoVs differently.

Further work is needed to confirm the clinical significance of these findings in humans. However, the data discussed herein suggest that ACE2 polymorphisms could determine human susceptibility to SARS-CoV-2 infection, particularly as they relate to ethnic and geographical differences.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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