TY - JOUR
T1 - ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population
AU - GEN-COVID Multicenter Study
AU - Benetti, Elisa
AU - Tita, Rossella
AU - Spiga, Ottavia
AU - Ciolfi, Andrea
AU - Birolo, Giovanni
AU - Bruselles, Alessandro
AU - Doddato, Gabriella
AU - Giliberti, Annarita
AU - Marconi, Caterina
AU - Musacchia, Francesco
AU - Pippucci, Tommaso
AU - Torella, Annalaura
AU - Trezza, Alfonso
AU - Valentino, Floriana
AU - Baldassarri, Margherita
AU - Brusco, Alfredo
AU - Asselta, Rosanna
AU - Bruttini, Mirella
AU - Furini, Simone
AU - Seri, Marco
AU - Nigro, Vincenzo
AU - Matullo, Giuseppe
AU - Tartaglia, Marco
AU - Mari, Francesca
AU - Renieri, Alessandra
AU - Pinto, Anna Maria
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
KW - Aged
KW - Angiotensin-Converting Enzyme 2
KW - Betacoronavirus/chemistry
KW - COVID-19
KW - Cohort Studies
KW - Coronavirus Infections/epidemiology
KW - Databases, Genetic
KW - Female
KW - Frameshift Mutation
KW - Genetic Predisposition to Disease
KW - Humans
KW - Italy/epidemiology
KW - Male
KW - Middle Aged
KW - Molecular Dynamics Simulation
KW - Mutation, Missense
KW - Pandemics
KW - Peptidyl-Dipeptidase A/chemistry
KW - Pneumonia, Viral/epidemiology
KW - Protein Stability
KW - SARS-CoV-2
KW - Spike Glycoprotein, Coronavirus/metabolism
KW - Whole Exome Sequencing
U2 - 10.1038/s41431-020-0691-z
DO - 10.1038/s41431-020-0691-z
M3 - Article
C2 - 32681121
VL - 28
SP - 1602
EP - 1614
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
SN - 1018-4813
IS - 11
ER -