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.
Highlights
In December 2019, a new infectious respiratory disease emerged in Wuhan, Hubei province, China [1,2,3]
It has been postulated that residues 31, 41, 82, 353, 355, and 357 of the angiotensin converting enzyme 2 (ACE2) receptor map to the surface of the protein interacting with SARS-CoV-2 spike protein [12], as previously documented for SARS-CoV
Taking advantage of the Network of Italian Genomes (NIG), a consortium established to generate a public database (NIG-db) containing aggregate variant frequencies data for the Italian population, here we describe the genetic variation of ACE2 in the Italian population, one of the newly affected countries by the SARS-CoV-2 outbreak causing COVID-19
Summary
In December 2019, a new infectious respiratory disease emerged in Wuhan, Hubei province, China [1,2,3]. Recent studies modeled the spike protein to identify the receptor for SARS-CoV-2 and indicated that angiotensin converting enzyme 2 (ACE2) is the receptor for this novel coronavirus [7, 8]. Cleavage of the C-terminal segment of ACE2 by proteases, such as transmembrane protease serine 2 (TMPRSS2), enhances the spike protein-driven viral entry [13, 14]. It is possible, in principle, that genetic variability of the ACE2 receptor is one of the elements modulating virion intake and disease severity. It is one of the genes escaping X inactivation several lines of evidence suggest that a different degree of X-chromosome inactivation (XCI) is present in distinct tissues [15]
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