ACE2 gene variants may underlie interindividual variability and susceptibility to COVID-19 in the Italian population
Authors: Benetti Elisa , Tita Rossella , Spiga Ottavia , Ciolfi Andrea , Birolo Giovanni , Bruselles Alessandro , Doddato Gabriella , Giliberti Annarita , Marconi Caterina , Musacchia Francesco , Pippucci Tommaso , Torella Annalaura , Trezza Alfonso , Valentino Floriana , Baldassarri Margherita , Brusco Alfredo , Asselta Rosanna , Bruttini Mirella , Furini Simone , Seri Marco , Nigro Vincenzo , Matullo Giuseppe , Tartaglia Marco , Mari Francesca ,   GEN-COVID Multicenter Study, Frullanti Elisa , Fallerini Chiara , Daga Sergio , Croci Susanna , Amitrano Sara , Fava Francesca , Montagnani Francesca , Di Sarno Laura , Tommasi Andrea , Palmieri Maria , Emiliozzi Arianna , Fabbiani Massimiliano , Rossetti Barbara , Zanelli Giacomo , Bergantini Laura , D’Alessandro Miriana , Cameli Paolo , Bennet David , Anedda Federico , Marcantonio Simona , Scolletta Sabino , Franchi Federico , Mazzei Maria Antonietta , Conticini Edoardo , Cantarini Luca , Frediani Bruno , Tacconi Danilo , Feri Marco , Scala Raffaele , Spargi Genni , Corridi Marta , Nencioni Cesira , Caldarelli Gian Piero , Spagnesi Maurizio , Piacentini Paolo , Bandini Maria , Desanctis Elena , Canaccini Anna , Spertilli Chiara , Donati Alice , Guidelli Luca , Croci Leonardo , Verzuri Agnese , Anemoli Valentina , Ognibene Agostino , Vaghi Massimo , D’Arminio Monforte Antonella , Merlini Esther , Mondelli Mario U. , Mantovani Stefania , Ludovisi Serena , Girardis Massimo , Venturelli Sophie , Sita Marco , Cossarizza Andrea , Antinori Andrea , Vergori Alessandra , Rusconi Stefano , Siano Matteo , Gabrieli Arianna , Riva Agostino , Francisci Daniela , Schiaroli Elisabetta , Scotton Pier Giorgio , Andretta Francesca , Panese Sandro , Scaggiante Renzo , Parisi Saverio Giuseppe , Castelli Francesco , Quiros-Roldan Maria Eugenia , Magro Paola , Minardi Cristina , Castelli Deborah , Polesini Itala , Della Monica Matteo , Piscopo Carmelo , Capasso Mario , Russo Roberta , Andolfo Immacolata , Iolascon Achille , Carella Massimo , Castori Marco , Merla Giuseppe , Aucella Filippo , Raggi Pamela , Marciano Carmen , Perna Rita , Bassetti Matteo , Di Biagio Antonio , Sanguinetti Maurizio , Masucci Luca , Gabbi Chiara , Valente Serafina , Guerrini Susanna , Meloni Ilaria , Mencarelli Maria Antonietta , Rizzo Caterina Lo , Bargagli Elena , Mandalà Marco , Giorli Alessia , Salerni Lorenzo , Fiorentino Giuseppe , Zucchi Patrizia , Parravicini Pierpaolo , Menatti Elisabetta , Baratti Stefano , Trotta Tullio , Giannattasio Ferdinando , Coiro Gabriella , Lena Fabio , Coviello Domenico A. , Mussini Cristina , Renieri Alessandra , Pinto Anna Maria 
Published: July 2020

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 forACE2variants. 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 ofACE2WES data between a cohort of 131 patients and 258 controls allowed identifying a statistically significant (Pvalue < 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.