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

2020; Springer Nature; Volume: 28; Issue: 11 Linguagem: Inglês

10.1038/s41431-020-0691-z

1476-5438

Elisa Benetti, Rossella Tita, Ottavia Spiga, Andrea Ciolfi, Giovanni Birolo, Alessandro Bruselles, Gabriella Doddato, Annarita Giliberti, Caterina Marconi, Francesco Musacchia, Tommaso Pippucci, Annalaura Torella, Alfonso Trezza, Floriana Valentino, Margherita Baldassarri, Alfredo Brusco, Rosanna Asselta, Mirella Bruttini, Simone Furini, Marco Seri, Vincenzo Nigro, Giuseppe Matullo, Marco Tartaglia, Francesca Mari, Elisa Frullanti, Chiara Fallerini, Sergio Daga, Susanna Croci, Sara Amitrano, Francesca Fava, Francesca Montagnani, Laura Di Sarno, Andrea Tommasi, Maria Palmieri, Arianna Emiliozzi, Massimiliano Fabbiani, Barbara Rossetti, Giacomo Zanelli, Laura Bergantini, Miriana d’Alessandro, Paolo Cameli, David Bennet, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Maria Antonietta Mazzei, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Marco Feri, Raffaele Scala, Genni Spargi, Marta Corridi, Cesira Nencioni, Gian Piero Caldarelli, Maurizio Spagnesi, Paolo Piacentini, Maria Bandini, Elena Desanctis, Anna Canaccini, Chiara Spertilli, Alice Donati, Luca Guidelli, Leonardo Croci, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Massimo Vaghi, Antonella d’Arminio Monforte, Esther Merlini, Mario U. Mondelli, Stefania Mantovani, Serena Ludovisi, Massimo Girardis, Sophie Venturelli, Marco Sita, Andrea Cossarizza, Andrea Antinori, Alessandra Vergori, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Saverio Giuseppe Parisi, Francesco Castelli, Eugenia Quirós-Roldán, Paola Magro, C Minardi, Deborah Castelli, Itala Polesini, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Massimo Carella, Marco Castori, Giuseppe Merla, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Chiara Gabbi, Serafina Valente, Susanna Guerrini, Ilaria Meloni, Maria Antonietta Mencarelli, Caterina Lo Rizzo, Elena Bargagli, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Giuseppe Fiorentino, Patrizia Zucchi, Pierpaolo Parravicini, E. Menatti, Stefano Baratti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Domenico Coviello, Cristina Mussini, Alessandra Renieri, Anna Maria Pinto,

PARP inhibition in cancer therapy

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.