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

Anno:

2020

ACE2 gene variants may underlie interindividual variability and susceptibility

Elisa Benetti # 1, Rossella Tita # 2, Ottavia Spiga 3, Andrea Ciolfi 4, Giovanni Birolo 5, Alessandro Bruselles 6, Gabriella Doddato 7, Annarita Giliberti 7, Caterina Marconi 8, Francesco Musacchia 9, Tommaso Pippucci 10, Annalaura Torella 11, Alfonso Trezza 3, Floriana Valentino 7, Margherita Baldassarri 7, Alfredo Brusco 5 12, Rosanna Asselta 13 14, Mirella Bruttini 2 7, Simone Furini 1, Marco Seri 8 10, Vincenzo Nigro 9 11, Giuseppe Matullo 5 12, Marco Tartaglia 4, Francesca Mari 2 7, GEN-COVID Multicenter Study; Alessandra Renieri 15 16, Anna Maria Pinto 2

Affiliations

1Department of Medical Biotechnologies, University of Siena, Siena, Italy.
2Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy.
3Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy.
4Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.
5Department of Medical Sciences, University of Turin, Turin, Italy.
6Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy.
7Medical Genetics, University of Siena, Siena, Italy.
8Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy.
9Telethon Institute of Genetics and Medicine, Pozzuoli, Italy.
10Sant'Orsola-Malpighi University Hospital, Bologna, Italy.
11Dipartimento di Medicina di Precisione, Università della Campania "Luigi Vanvitelli", Napoli, Italy.
12Genetica Medica, Città della Salute e della Scienza, Torino, Italy.
13Department of Biomedical Sciences, Humanitas University, Rozzano, Milan, Italy.
14Humanitas Clinical and Research Center-IRCCS, Rozzano, Milan, Italy.
15Genetica Medica, Azienda Ospedaliera Universitaria Senese, Siena, Italy. alessandra.renieri@unisi.it.
16Medical Genetics, University of Siena, Siena, Italy. alessandra.renieri@unisi.it.
# Contributed equally

Eur J Hum Genet. 2020 Nov;28(11):1602-1614. doi: 10.1038/s41431-020-0691-z. Epub 2020 Jul 17.

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.