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.
【저자키워드】 viral infection, Genome assembly algorithms, 【초록키워드】 COVID-19, coronavirus disease, SARS-CoV-2, ACE2, coronavirus, Pneumonia, susceptibility, severity, angiotensin converting enzyme 2, whole-exome sequencing, variant, Infection, risk, Italy, angiotensin converting enzyme, variants, Spike protein, Risk assessment, Novel coronavirus, Spread, Protein, Cohort, Coronavirus disease-19, SARS-CoV-2 spike protein, Wuhan, Patient, Control, Cluster, protein structure, network, protein stability, preventive measures, disease, patients, Protein binding, binding, therapeutic options, Clinical severity, Endemic, angiotensin, Missense, ACE2 variants, host proteases, disease susceptibility, reason for, preventive measure, p value, changes, Rare variants, Asian, enzyme, host receptor, individual, Variability, host protease, human-to-human transmission, internalization, reason, bilateral pneumonia, genetic background, clinical variability, FIVE, Italian, Cell, interstitial, European country, Wuhan, China, initial, shown, described, predicted, contribute, interfere, allelic, statistically significant, Taking, assumed, NIG, WES, with COVID-19, 【제목키워드】 COVID-19, ACE2, susceptibility, variant, Variability, Italian population, underlie,