SARS-CoV-2 infection susceptibility influenced by ACE2 genetic polymorphisms: insights from Tehran Cardio-Metabolic Genetic Study

Abstract

The genetic variations among individuals are one of the notable factors determining disease severity and drug response. Nowadays, COVID-19 pandemic has been adversely affecting many aspects of human life. We used the Tehran Cardio-Metabolic Genetic Study (TCGS) data that is an ongoing genetic study including the whole-genome sequencing of 1200 individuals and chip genotyping of more than 15,000 participants. Here, the effect of ACE2 variations by focusing on the receptor-binding site of SARS-CoV-2 and ACE2 cleavage by TMPRSS2 protease were investigated through simulations study. After analyzing TCGS data, 570 genetic variations on the ACE2 gene, including single nucleotide polymorphisms (SNP) and insertion/deletion (INDEL) were detected. Interestingly, two observed missense variants, K26R and S331F, which only the first one was previously reported, can reduce the receptor affinity for the viral Spike protein. Moreover, our bioinformatics simulation of 3D structures and docking of proteins explains important details of ACE2-Spike and ACE2-TMPRSS2 interactions, especially the critical role of Arg652 of ACE2 for protease function of TMPRSS2 was uncovered. As our results show that the genetic variation of ACE2 can at least influence the affinity of this receptor to its partners, we need to consider the genetic variations on ACE2 as well as other genes in the pathways that contribute to the pathogenesis of COVID-19 for designing efficient drugs and vaccines.

Interplay between SARS‐CoV‐2 and human long non‐coding RNAs

“…The recent outbreak of COVID‐19 has been leading to an increased number of infected individuals and subsequent mortality worldwide. Although genomic variants can cause differences in the symptoms and contagion of SARS‐CoV‐2 infection, 1 it is essential to evaluate the various aspects of viral pathogenesis to understand the biological pathways relevant to the COVID‐19 pandemic. Long non‐coding RNAs (lncRNAs), RNA molecules longer than 200 nucleotides, can serve as diagnostic biomarkers or therapeutic targets for many diseases.…”

Host polymorphisms and COVID-19 infection

“…Molecular dynamic demonstrated that I468V and K26R may affect binding characteristics between the S protein of the virus and the human ACE2 receptor [16] . Besides K26R, a specific SNP (S331F) was identified in the Iranian population, which could reduce the receptor affinity for the viral Spike protein [17] . DOCK and FireDock simulations identified 6 ACE2 missense variants (A25T, E37K, E75G, I21T, K26R, T55A) with higher affinity for SARS-CoV-2 Spike protein receptor-binding domain for wild type ACE2, and 11 variants (E23K, E35K, I21V, K26E, K68E, M82I, N51D, N58H, S43R, T27A, Y50F) with a lower affinity [18] .…”

Hypertension, Obesity, and COVID-19: a Collision of Pandemics

“…The latest research on the role of the RAAS pathway in COVID-19 focuses on genetic variations in ACE2 expression among individuals [ 21 ]. A publication by Lanjanian et al [ 21 ] found that some missense variants of the ACE2 receptor have reduced affinity for the COVID-19 spike protein that gains entry into cells. Further investigation in this area may help target future therapies for COVID-19.…”