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.

Analysis of the Spectrum of ACE2 Variation Suggests a Possible Influence of Rare and Common Variants on Susceptibility to COVID-19 and Severity of Outcome

“…Notably, the total frequency of missense variants in the SEU population was the lowest (0.022), being more similar to the frequency in the East Asian population and Estonians ( Supplementary Table S6 and Figures 1C,D ). The low frequency of missense variants in the SEU population suggests that missense variants might play a protective role against COVID-19 infection (a similar hypothesis has been made by Benetti et al (2020) . Surprisingly, the differences between populations are reversed when considering missense variants predicted as deleterious by PROVEAN ( Choi and Chan, 2015 ), SIFT ( Ng and Henikoff, 2001 ), FATHMM ( Shihab et al, 2013 ), and PolyPhen2 ( Adzhubei et al, 2010 ; Supplementary Table S7 and Figure 1E ).…”

“…Furthermore, the first study ( Cao et al, 2020 ) did not discuss the ACE2 gene polymorphism in different European subpopulations. Recent whole-exome sequencing (WES)-based studies in such countries as Italy also aimed at the identification of the genetic COVID-19 susceptibility factors, with some missense ACE2 variants shown to have a protective role ( Benetti et al, 2020 ). The comprehensive study of the ACE2 variations focused on the possible protective pathogenic mutations revealed that missense mutations affecting protein interaction with S-protein exhibit overall low frequency due to the absence of natural selection with no discernable differences between populations ( Stawiski et al, 2020 ).…”

Broad host range of SARS-CoV-2 predicted by comparative and structural analysis of ACE2 in vertebrates

“…We examined the variation in ACE2 binding residues within humans, some of which have been proposed to alter binding affinity ( 17 , 23 – 26 ). We integrated data from six different sources, dbSNP, 1KGP, Topmed, UK10K, gnomAD, and CHINAMAP, and identified a total of 11 variants in 10 of the 25 ACE2 binding residues ( Dataset S2 ).…”

Describing variability in pig genes involved in coronavirus infections: towards a One Health perspective in conservation of animal genetic resources

“…Structural variations and different expression levels of the receptors and S protein priming proteases could potentially affect the spike/receptor interactions and subsequent spike cleavage e ciency which might cause differences of susceptibility of the host for the coronavirus infection capability and disease progression. A few studies in humans that investigated the ACE2 and TMPRSS2 genes reported variants segregating in different cohorts that might confer resistance against SARS-CoV-2 infection or modulate COVID-19 severity [ [48][49][50][51][52][53].…”

“…Epidemiological, biological and virological characteristics of coronaviruses, including their demonstrated ability to easily cross species barriers, suggest that pets and livestock should be considered as part of a global control and of a "One Health" approach to evaluate if animals that are close to human contacts could represent a risk source of infections for humans and vice versa [ [62][63]. Based on the mentioned preliminary evidences on the potential relationships between SARS-CoV-2 and pigs (even if contrasting) and considering i) the relevance of the pig production systems for meat supply, ii) that several other coronaviruses circulate in pigs and cause diseases in this livestock species [7][8]40 ], iii) that receptor variants may confer different susceptibility to infections within species [ [48][49][50][51][52][53], iv) that coronaviruses may jump the species barriers easily [ 5,18,46,57 ] and v) that variability of the RBD region of the spike protein might determine a quite large host spectrum for every coronaviruses [ 45,64 ], as part of a "One Health" approach [ 63 ], it is needed to evaluate the genetic variability segregating in pig populations potentially conferring differences of sensitivity to coronavirus-related diseases.…”