ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population

Abstract

In December 2019, an initial cluster of interstitial bilateral pneumonia emerged in Wuhan, China. A human-to-human transmission was assumed and a previously unrecognized entity, termed coronavirus disease-19 (COVID-19) due to a novel coronavirus (SARS-CoV-2) was described. The infection has rapidly spread out all over the world and Italy has been the first European country experiencing the endemic wave with unexpected clinical severity in comparison with Asian countries. It has been shown that SARS-CoV-2 utilizes angiotensin converting enzyme 2 (ACE2) as host receptor and host proteases for cell surface binding and internalization. Thus, a predisposing genetic background can give reason for interindividual disease susceptibility and/or severity. Taking advantage of the Network of Italian Genomes (NIG), here we mined whole-exome sequencing data of 6930 Italian control individuals from five different centers looking for ACE2 variants. A number of variants with a potential impact on protein stability were identified. Among these, three more common missense changes, p.(Asn720Asp), p.(Lys26Arg), and p.(Gly211Arg) were predicted to interfere with protein structure and stabilization. Rare variants likely interfering with the internalization process, namely p.(Leu351Val) and p.(Pro389His), predicted to interfere with SARS-CoV-2 spike protein binding, were also observed. Comparison of ACE2 WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (P value < 0.029) higher allelic variability in controls compared with patients. These findings suggest that a predisposing genetic background may contribute to the observed interindividual clinical variability associated with COVID-19, allowing an evidence-based risk assessment leading to personalized preventive measures and therapeutic options.

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1. ACE2 crystal structure with PDB ID 1R42.

Surface and cartoon representations of protein in gray. In blue stick are represented each single mutated positions, cartoon region in yellow represent segment between amino acid 30–41, cartoon in green represent segment between amino acid 353–357 and cartoon in red represent segment between amino acid 82–84 that are protein regions responsible of interaction with 2019-nCOv spike glycoprotein.

Fig. 2. ACE2 wild-type and variants superimposed structures after 100 ns MD simulation.

Cartoon representation of ACE2 wild type (orange) and variants (green) in blue sticks the wild-type residues while in red the corresponding variants. In cyan and pink sticks residues interacting with each specific position.

Fig. 3. Structure superimposition snapshot between wild-type protein and variant proteins.

a Root mean square deviation (RMSD) trends for the backbone of ACE2 WT (black line) and some selected variants (colored lines, see legend) during 100 ns of simulation. The molecular dynamics simulation shows a good stability for all systems with exception of G211R mutants. RMSD is a parameter used to define the stability of an element. Wild type shows a steady course in the RMSD value, stabilizing at an average of 0.2 nm, while, the G211R variant shows a gradual increase in RMSD value, stabilizing at an average of 0.6 nm. b SASA graphical representation of ACE2 WT (black line) and ACE2 variants (colored lines, see legend).

Fig. 4. Differences in ACE2 variants in COVID-19 patients compared with controls.

The figure shows the variants located in the ACE2 protein domains. The variants present in controls are shown in black while the variants in cases are shown in red. The number of patients carrying the variant is shown in brackets.