C9orf72 intermediate repeats confer genetic risk for severe covid-19 pneumonia independently of age

Isabella Zanella; Eliana Zacchi; Simone Piva; Massimiliano Filosto; Giada Beligni; Diana Alaverdian; Sara Amitrano; Francesca Fava; Margherita Baldassarri; Elisa Frullanti; Ilaria Meloni; Alessandra Renieri; Francesco Castelli; Eugenia Quiros-Roldan; Francesca Mari; Sergio Daga; Elisa Benetti; Simone Furini; Chiara Fallerini; Floriana Valentino; Francesca Valentino; Gabriella Doddato; Annarita Giliberti; Rossella Tita; Mirella Bruttini; Susanna Croci; Anna Maria Pinto; Maria Antonietta Mencarelli; Marta Mencarelli; Caterina Lo Rizzo; Francesca Montagnani; Mario Tumbarello; Ilaria Rancan; Laura Di Sarno; Maria Palmieri; Marco Palmieri; Miriam Lucia Carriero; Massimiliano Fabbiani; Barbara Rossetti; Elena Bargagli; Laura Bergantini; Miriana D’Alessandro; Michele D'Alessandro; Paolo Cameli; David Bennett; Federico Anedda; Simona Marcantonio; Sabino Scolletta; Federico Franchi; Francesca Franchi; Maria Antonietta Mazzei; Susanna Guerrini; Edoardo Conticini; Luca Cantarini; Bruno Frediani; Danilo Tacconi; Chiara Spertilli Raffaelli; Marco Feri; Alice Donati; Andrea Donati; Raffaele Scala; Luca Guidelli; Genni Spargi; Marta Corridi; Cesira Nencioni; Leonardo Croci; Gian Piero Caldarelli; Maurizio Spagnesi; Paolo Piacentini; Maria Bandini; Elena Desanctis; Silvia Cappelli; Anna Canac-Cini; Agnese Verzuri; Valentina Anemoli; Agostino Ognibene; Alessandro Pancrazi; Maria Lorubbio; Massimo Vaghi; Antonella D’Arminio Monforte; Federica Gaia Miraglia; Mario U. Mondelli; Raffaele Bruno; Vecchia Marco; Stefania Mantovani; Susanna Mantovani; Serena Ludovisi; Massimo Girardis; Sophie Venturelli; Stefano Busani; Andrea Cossarizza; Armando Antinori; Alessandra Vergori; Arianna Emiliozzi; Stefano Rusconi; Matteo Siano; Arianna Gabrieli; Agostino Riva; Daniela Francisci; Elisabetta Schiaroli; Andrea Tommasi; Francesco Paciosi; Pier Giorgio Scotton; Francesca Andretta; Sandro Panese; Renzo Scaggiante; Francesca Gatti; Saverio Giuseppe Parisi; Melania Degli Antoni; Matteo Della Monica; Carmelo Piscopo; Mario Capasso; Monica Capasso; Roberta Russo; Immacolata Andolfo; Achille Iolascon; Giuseppe Fiorentino; Massimo Carella; Marco Castori; Giuseppe Merla; Gabriella Maria Squeo; Filippo Aucella; Pamela Raggi; Carmen Marciano; Rita Perna; Raffaella Perna; Matteo Bassetti; Antonio Di Biagio; Maurizio Sanguinetti; Luca Masucci; Serafina Valente; Marco Mandalà; Alessia Giorli; Lorenzo Salerni; Patrizia Zucchi; Pierpaolo Parravicini; Elisabetta Menatti; Stefano Baratti; Tullio Trotta; Ferdinando Giannattasio; Gabriella Coiro; Fabio Lena; Francesco Lena; Domenico A. Coviello; Cristina Mussini; Giancarlo Bosio; Giacomo Bosio; Enrico Martinelli; Sandro Mancarella; Luisa Tavecchia; Mary Ann Belli; Lia Crotti; Gianfranco Parati; Nicola Picchiotti; Marco Gori; Mario Gori; Chiara Gabbi; Maurizio Sanarico; Stefano Ceri; Pietro Pinoli; Francesco Raimondi; Filippo Bis-Carini; Alessandra Stella; Marco Rizzi; Franco Maggiolo; Diego Ripamonti; Claudia Suardi; Tiziana Bachetti; Maria Teresa La Rovere; Simona Sarzi-Braga; Maurizio Bussotti; Katia Capitani; Kristina Zguro; Simona Dei; Sabrina Ravaglia; Rosangela Artuso; Antonio Perrella; Francesco Bianchi; Paola Bergomi; Emanuele Catena; Riccardo Colombo; Valentina Perticaroli; Massimo Gennarelli; Chiara Magri; Carlotta Magri'; Giorgio Basiotto; Daniela Zizioli; Silvia Giliani; Eugenio Monti; Emanuele Focà; Cannio Carriero; Nicola Latronico; Alessandro Padovani; Duilio Brugnoni

doi:10.3390/ijms22136991

C9orf72 intermediate repeats confer genetic risk for severe covid-19 pneumonia independently of age

Isabella Zanella, Eliana Zacchi, Simone Piva, Massimiliano Filosto, Giada Beligni, Diana Alaverdian, Sara Amitrano, Francesca Fava, Margherita Baldassarri, Elisa Frullanti, Ilaria Meloni, Alessandra Renieri, Francesco Castelli, Eugenia Quiros-Roldan, Francesca Mari, Sergio Daga, Elisa Benetti, Simone Furini, Chiara Fallerini, Floriana ValentinoFrancesca Valentino, Gabriella Doddato, Annarita Giliberti, Rossella Tita, Mirella Bruttini, Susanna Croci, Anna Maria Pinto, Maria Antonietta Mencarelli, Marta Mencarelli, Caterina Lo Rizzo, Francesca Montagnani, Mario Tumbarello, Ilaria Rancan, Laura Di Sarno, Maria Palmieri, Marco Palmieri, Miriam Lucia Carriero, Massimiliano Fabbiani, Barbara Rossetti, Elena Bargagli, Laura Bergantini, Miriana D’Alessandro, Michele D'Alessandro, Paolo Cameli, David Bennett, Federico Anedda, Simona Marcantonio, Sabino Scolletta, Federico Franchi, Francesca Franchi, Maria Antonietta Mazzei, Susanna Guerrini, Edoardo Conticini, Luca Cantarini, Bruno Frediani, Danilo Tacconi, Chiara Spertilli Raffaelli, Marco Feri, Alice Donati, Andrea Donati, Raffaele Scala, Luca Guidelli, Genni Spargi, Marta Corridi, Cesira Nencioni, Leonardo Croci, Gian Piero Caldarelli, Maurizio Spagnesi, Paolo Piacentini, Maria Bandini, Elena Desanctis, Silvia Cappelli, Anna Canac-Cini, Agnese Verzuri, Valentina Anemoli, Agostino Ognibene, Alessandro Pancrazi, Maria Lorubbio, Massimo Vaghi, Antonella D’Arminio Monforte, Federica Gaia Miraglia, Mario U. Mondelli, Raffaele Bruno, Vecchia Marco, Stefania Mantovani, Susanna Mantovani, Serena Ludovisi, Massimo Girardis, Sophie Venturelli, Stefano Busani, Andrea Cossarizza, Armando Antinori, Alessandra Vergori, Arianna Emiliozzi, Stefano Rusconi, Matteo Siano, Arianna Gabrieli, Agostino Riva, Daniela Francisci, Elisabetta Schiaroli, Andrea Tommasi, Francesco Paciosi, Pier Giorgio Scotton, Francesca Andretta, Sandro Panese, Renzo Scaggiante, Francesca Gatti, Saverio Giuseppe Parisi, Melania Degli Antoni, Matteo Della Monica, Carmelo Piscopo, Mario Capasso, Monica Capasso, Roberta Russo, Immacolata Andolfo, Achille Iolascon, Giuseppe Fiorentino, Massimo Carella, Marco Castori, Giuseppe Merla, Gabriella Maria Squeo, Filippo Aucella, Pamela Raggi, Carmen Marciano, Rita Perna, Raffaella Perna, Matteo Bassetti, Antonio Di Biagio, Maurizio Sanguinetti, Luca Masucci, Serafina Valente, Marco Mandalà, Alessia Giorli, Lorenzo Salerni, Patrizia Zucchi, Pierpaolo Parravicini, Elisabetta Menatti, Stefano Baratti, Tullio Trotta, Ferdinando Giannattasio, Gabriella Coiro, Fabio Lena, Francesco Lena, Domenico A. Coviello, Cristina Mussini, Giancarlo Bosio, Giacomo Bosio, Enrico Martinelli, Sandro Mancarella, Luisa Tavecchia, Mary Ann Belli, Lia Crotti, Gianfranco Parati, Nicola Picchiotti, Marco Gori, Mario Gori, Chiara Gabbi, Maurizio Sanarico, Stefano Ceri, Pietro Pinoli, Francesco Raimondi, Filippo Bis-Carini, Alessandra Stella, Marco Rizzi, Franco Maggiolo, Diego Ripamonti, Claudia Suardi, Tiziana Bachetti, Maria Teresa La Rovere, Simona Sarzi-Braga, Maurizio Bussotti, Katia Capitani, Kristina Zguro, Simona Dei, Sabrina Ravaglia, Rosangela Artuso, Antonio Perrella, Francesco Bianchi, Paola Bergomi, Emanuele Catena, Riccardo Colombo, Valentina Perticaroli, Massimo Gennarelli, Chiara Magri, Carlotta Magri', Giorgio Basiotto, Daniela Zizioli, Silvia Giliani, Eugenio Monti, Emanuele Focà, Cannio Carriero, Nicola Latronico, Alessandro Padovani, Duilio Brugnoni

Research output: Contribution to journal › Article

Abstract

A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lyso-some functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.

Original language	English
Pages (from-to)	6991-N/A
Journal	International Journal of Molecular Sciences
Volume	22
DOIs	https://doi.org/10.3390/ijms22136991
Publication status	Published - 2021

Keywords

Autophagy
C9orf72
COVID-19
Genetic risk
Innate immunity
Intermediate alleles
SARS-CoV-2

Access to Document

10.3390/ijms22136991

Cite this

Zanella, I., Zacchi, E., Piva, S., Filosto, M., Beligni, G., Alaverdian, D., Amitrano, S., Fava, F., Baldassarri, M., Frullanti, E., Meloni, I., Renieri, A., Castelli, F., Quiros-Roldan, E., Mari, F., Daga, S., Benetti, E., Furini, S., Fallerini, C., ... Brugnoni, D. (2021). C9orf72 intermediate repeats confer genetic risk for severe covid-19 pneumonia independently of age. International Journal of Molecular Sciences, 22, 6991-N/A. https://doi.org/10.3390/ijms22136991

@article{d503946d807d413693028051798bc427,

title = "C9orf72 intermediate repeats confer genetic risk for severe covid-19 pneumonia independently of age",

abstract = "A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lyso-some functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.",

keywords = "Autophagy, C9orf72, COVID-19, Genetic risk, Innate immunity, Intermediate alleles, SARS-CoV-2, Autophagy, C9orf72, COVID-19, Genetic risk, Innate immunity, Intermediate alleles, SARS-CoV-2",

author = "Isabella Zanella and Eliana Zacchi and Simone Piva and Massimiliano Filosto and Giada Beligni and Diana Alaverdian and Sara Amitrano and Francesca Fava and Margherita Baldassarri and Elisa Frullanti and Ilaria Meloni and Alessandra Renieri and Francesco Castelli and Eugenia Quiros-Roldan and Francesca Mari and Sergio Daga and Elisa Benetti and Simone Furini and Chiara Fallerini and Floriana Valentino and Francesca Valentino and Gabriella Doddato and Annarita Giliberti and Rossella Tita and Mirella Bruttini and Susanna Croci and Pinto, {Anna Maria} and Mencarelli, {Maria Antonietta} and Marta Mencarelli and Rizzo, {Caterina Lo} and Francesca Montagnani and Mario Tumbarello and Ilaria Rancan and Sarno, {Laura Di} and Maria Palmieri and Marco Palmieri and Carriero, {Miriam Lucia} and Massimiliano Fabbiani and Barbara Rossetti and Elena Bargagli and Laura Bergantini and Miriana D{\textquoteright}Alessandro and Michele D'Alessandro and Paolo Cameli and David Bennett and Federico Anedda and Simona Marcantonio and Sabino Scolletta and Federico Franchi and Francesca Franchi and Mazzei, {Maria Antonietta} and Susanna Guerrini and Edoardo Conticini and Luca Cantarini and Bruno Frediani and Danilo Tacconi and Raffaelli, {Chiara Spertilli} and Marco Feri and Alice Donati and Andrea Donati and Raffaele Scala and Luca Guidelli and Genni Spargi and Marta Corridi and Cesira Nencioni and Leonardo Croci and Caldarelli, {Gian Piero} and Maurizio Spagnesi and Paolo Piacentini and Maria Bandini and Elena Desanctis and Silvia Cappelli and Anna Canac-Cini and Agnese Verzuri and Valentina Anemoli and Agostino Ognibene and Alessandro Pancrazi and Maria Lorubbio and Massimo Vaghi and Monforte, {Antonella D{\textquoteright}Arminio} and Miraglia, {Federica Gaia} and Mondelli, {Mario U.} and Raffaele Bruno and Vecchia Marco and Stefania Mantovani and Susanna Mantovani and Serena Ludovisi and Massimo Girardis and Sophie Venturelli and Stefano Busani and Andrea Cossarizza and Armando Antinori and Alessandra Vergori and Arianna Emiliozzi and Stefano Rusconi and Matteo Siano and Arianna Gabrieli and Agostino Riva and Daniela Francisci and Elisabetta Schiaroli and Andrea Tommasi and Francesco Paciosi and Scotton, {Pier Giorgio} and Francesca Andretta and Sandro Panese and Renzo Scaggiante and Francesca Gatti and Parisi, {Saverio Giuseppe} and Antoni, {Melania Degli} and Monica, {Matteo Della} and Carmelo Piscopo and Mario Capasso and Monica Capasso and Roberta Russo and Immacolata Andolfo and Achille Iolascon and Giuseppe Fiorentino and Massimo Carella and Marco Castori and Giuseppe Merla and Squeo, {Gabriella Maria} and Filippo Aucella and Pamela Raggi and Carmen Marciano and Rita Perna and Raffaella Perna and Matteo Bassetti and Biagio, {Antonio Di} and Maurizio Sanguinetti and Luca Masucci and Serafina Valente and Marco Mandal{\`a} and Alessia Giorli and Lorenzo Salerni and Patrizia Zucchi and Pierpaolo Parravicini and Elisabetta Menatti and Stefano Baratti and Tullio Trotta and Ferdinando Giannattasio and Gabriella Coiro and Fabio Lena and Francesco Lena and Coviello, {Domenico A.} and Cristina Mussini and Giancarlo Bosio and Giacomo Bosio and Enrico Martinelli and Sandro Mancarella and Luisa Tavecchia and Belli, {Mary Ann} and Lia Crotti and Gianfranco Parati and Nicola Picchiotti and Marco Gori and Mario Gori and Chiara Gabbi and Maurizio Sanarico and Stefano Ceri and Pietro Pinoli and Francesco Raimondi and Filippo Bis-Carini and Alessandra Stella and Marco Rizzi and Franco Maggiolo and Diego Ripamonti and Claudia Suardi and Tiziana Bachetti and Rovere, {Maria Teresa La} and Simona Sarzi-Braga and Maurizio Bussotti and Katia Capitani and Kristina Zguro and Simona Dei and Sabrina Ravaglia and Rosangela Artuso and Antonio Perrella and Francesco Bianchi and Paola Bergomi and Emanuele Catena and Riccardo Colombo and Valentina Perticaroli and Massimo Gennarelli and Chiara Magri and Carlotta Magri' and Giorgio Basiotto and Daniela Zizioli and Silvia Giliani and Eugenio Monti and Emanuele Foc{\`a} and Cannio Carriero and Nicola Latronico and Alessandro Padovani and Duilio Brugnoni",

year = "2021",

doi = "10.3390/ijms22136991",

language = "English",

volume = "22",

pages = "6991--N/A",

journal = "International Journal of Molecular Sciences",

issn = "1661-6596",

publisher = "Multidisciplinary Digital Publishing Institute (MDPI)",

}

Zanella, I, Zacchi, E, Piva, S, Filosto, M, Beligni, G, Alaverdian, D, Amitrano, S, Fava, F, Baldassarri, M, Frullanti, E, Meloni, I, Renieri, A, Castelli, F, Quiros-Roldan, E, Mari, F, Daga, S, Benetti, E, Furini, S, Fallerini, C, Valentino, F, Valentino, F, Doddato, G, Giliberti, A, Tita, R, Bruttini, M, Croci, S, Pinto, AM, Mencarelli, MA, Mencarelli, M, Rizzo, CL, Montagnani, F, Tumbarello, M, Rancan, I, Sarno, LD, Palmieri, M, Palmieri, M, Carriero, ML, Fabbiani, M, Rossetti, B, Bargagli, E, Bergantini, L, D’Alessandro, M, D'Alessandro, M, Cameli, P, Bennett, D, Anedda, F, Marcantonio, S, Scolletta, S, Franchi, F, Franchi, F, Mazzei, MA, Guerrini, S, Conticini, E, Cantarini, L, Frediani, B, Tacconi, D, Raffaelli, CS, Feri, M, Donati, A, Donati, A, Scala, R, Guidelli, L, Spargi, G, Corridi, M, Nencioni, C, Croci, L, Caldarelli, GP, Spagnesi, M, Piacentini, P, Bandini, M, Desanctis, E, Cappelli, S, Canac-Cini, A, Verzuri, A, Anemoli, V, Ognibene, A, Pancrazi, A, Lorubbio, M, Vaghi, M, Monforte, ADA, Miraglia, FG, Mondelli, MU, Bruno, R, Marco, V, Mantovani, S, Mantovani, S, Ludovisi, S, Girardis, M, Venturelli, S, Busani, S, Cossarizza, A, Antinori, A, Vergori, A, Emiliozzi, A, Rusconi, S, Siano, M, Gabrieli, A, Riva, A, Francisci, D, Schiaroli, E, Tommasi, A, Paciosi, F, Scotton, PG, Andretta, F, Panese, S, Scaggiante, R, Gatti, F, Parisi, SG, Antoni, MD, Monica, MD, Piscopo, C, Capasso, M, Capasso, M, Russo, R, Andolfo, I, Iolascon, A, Fiorentino, G, Carella, M, Castori, M, Merla, G, Squeo, GM, Aucella, F, Raggi, P, Marciano, C, Perna, R, Perna, R, Bassetti, M, Biagio, AD, Sanguinetti, M , Masucci, L, Valente, S, Mandalà, M, Giorli, A, Salerni, L, Zucchi, P, Parravicini, P, Menatti, E, Baratti, S, Trotta, T, Giannattasio, F, Coiro, G, Lena, F, Lena, F, Coviello, DA, Mussini, C, Bosio, G, Bosio, G, Martinelli, E, Mancarella, S, Tavecchia, L, Belli, MA, Crotti, L, Parati, G, Picchiotti, N, Gori, M, Gori, M, Gabbi, C, Sanarico, M, Ceri, S, Pinoli, P, Raimondi, F, Bis-Carini, F, Stella, A, Rizzi, M, Maggiolo, F, Ripamonti, D, Suardi, C, Bachetti, T, Rovere, MTL, Sarzi-Braga, S, Bussotti, M, Capitani, K, Zguro, K, Dei, S, Ravaglia, S, Artuso, R, Perrella, A, Bianchi, F, Bergomi, P, Catena, E, Colombo, R, Perticaroli, V, Gennarelli, M, Magri, C, Magri', C, Basiotto, G, Zizioli, D, Giliani, S, Monti, E, Focà, E, Carriero, C, Latronico, N, Padovani, A & Brugnoni, D 2021, 'C9orf72 intermediate repeats confer genetic risk for severe covid-19 pneumonia independently of age', International Journal of Molecular Sciences, vol. 22, pp. 6991-N/A. https://doi.org/10.3390/ijms22136991

TY - JOUR

T1 - C9orf72 intermediate repeats confer genetic risk for severe covid-19 pneumonia independently of age

AU - Zanella, Isabella

AU - Zacchi, Eliana

AU - Piva, Simone

AU - Filosto, Massimiliano

AU - Beligni, Giada

AU - Alaverdian, Diana

AU - Amitrano, Sara

AU - Fava, Francesca

AU - Baldassarri, Margherita

AU - Frullanti, Elisa

AU - Meloni, Ilaria

AU - Renieri, Alessandra

AU - Castelli, Francesco

AU - Quiros-Roldan, Eugenia

AU - Mari, Francesca

AU - Daga, Sergio

AU - Benetti, Elisa

AU - Furini, Simone

AU - Fallerini, Chiara

AU - Valentino, Floriana

AU - Valentino, Francesca

AU - Doddato, Gabriella

AU - Giliberti, Annarita

AU - Tita, Rossella

AU - Bruttini, Mirella

AU - Croci, Susanna

AU - Pinto, Anna Maria

AU - Mencarelli, Maria Antonietta

AU - Mencarelli, Marta

AU - Rizzo, Caterina Lo

AU - Montagnani, Francesca

AU - Tumbarello, Mario

AU - Rancan, Ilaria

AU - Sarno, Laura Di

AU - Palmieri, Maria

AU - Palmieri, Marco

AU - Carriero, Miriam Lucia

AU - Fabbiani, Massimiliano

AU - Rossetti, Barbara

AU - Bargagli, Elena

AU - Bergantini, Laura

AU - D’Alessandro, Miriana

AU - D'Alessandro, Michele

AU - Cameli, Paolo

AU - Bennett, David

AU - Anedda, Federico

AU - Marcantonio, Simona

AU - Scolletta, Sabino

AU - Franchi, Federico

AU - Franchi, Francesca

AU - Mazzei, Maria Antonietta

AU - Guerrini, Susanna

AU - Conticini, Edoardo

AU - Cantarini, Luca

AU - Frediani, Bruno

AU - Tacconi, Danilo

AU - Raffaelli, Chiara Spertilli

AU - Feri, Marco

AU - Donati, Alice

AU - Donati, Andrea

AU - Scala, Raffaele

AU - Guidelli, Luca

AU - Spargi, Genni

AU - Corridi, Marta

AU - Nencioni, Cesira

AU - Croci, Leonardo

AU - Caldarelli, Gian Piero

AU - Spagnesi, Maurizio

AU - Piacentini, Paolo

AU - Bandini, Maria

AU - Desanctis, Elena

AU - Cappelli, Silvia

AU - Canac-Cini, Anna

AU - Verzuri, Agnese

AU - Anemoli, Valentina

AU - Ognibene, Agostino

AU - Pancrazi, Alessandro

AU - Lorubbio, Maria

AU - Vaghi, Massimo

AU - Monforte, Antonella D’Arminio

AU - Miraglia, Federica Gaia

AU - Mondelli, Mario U.

AU - Bruno, Raffaele

AU - Marco, Vecchia

AU - Mantovani, Stefania

AU - Mantovani, Susanna

AU - Ludovisi, Serena

AU - Girardis, Massimo

AU - Venturelli, Sophie

AU - Busani, Stefano

AU - Cossarizza, Andrea

AU - Antinori, Armando

AU - Vergori, Alessandra

AU - Emiliozzi, Arianna

AU - Rusconi, Stefano

AU - Siano, Matteo

AU - Gabrieli, Arianna

AU - Riva, Agostino

AU - Francisci, Daniela

AU - Schiaroli, Elisabetta

AU - Tommasi, Andrea

AU - Paciosi, Francesco

AU - Scotton, Pier Giorgio

AU - Andretta, Francesca

AU - Panese, Sandro

AU - Scaggiante, Renzo

AU - Gatti, Francesca

AU - Parisi, Saverio Giuseppe

AU - Antoni, Melania Degli

AU - Monica, Matteo Della

AU - Piscopo, Carmelo

AU - Capasso, Mario

AU - Capasso, Monica

AU - Russo, Roberta

AU - Andolfo, Immacolata

AU - Iolascon, Achille

AU - Fiorentino, Giuseppe

AU - Carella, Massimo

AU - Castori, Marco

AU - Merla, Giuseppe

AU - Squeo, Gabriella Maria

AU - Aucella, Filippo

AU - Raggi, Pamela

AU - Marciano, Carmen

AU - Perna, Rita

AU - Perna, Raffaella

AU - Bassetti, Matteo

AU - Biagio, Antonio Di

AU - Sanguinetti, Maurizio

AU - Masucci, Luca

AU - Valente, Serafina

AU - Mandalà, Marco

AU - Giorli, Alessia

AU - Salerni, Lorenzo

AU - Zucchi, Patrizia

AU - Parravicini, Pierpaolo

AU - Menatti, Elisabetta

AU - Baratti, Stefano

AU - Trotta, Tullio

AU - Giannattasio, Ferdinando

AU - Coiro, Gabriella

AU - Lena, Fabio

AU - Lena, Francesco

AU - Coviello, Domenico A.

AU - Mussini, Cristina

AU - Bosio, Giancarlo

AU - Bosio, Giacomo

AU - Martinelli, Enrico

AU - Mancarella, Sandro

AU - Tavecchia, Luisa

AU - Belli, Mary Ann

AU - Crotti, Lia

AU - Parati, Gianfranco

AU - Picchiotti, Nicola

AU - Gori, Marco

AU - Gori, Mario

AU - Gabbi, Chiara

AU - Sanarico, Maurizio

AU - Ceri, Stefano

AU - Pinoli, Pietro

AU - Raimondi, Francesco

AU - Bis-Carini, Filippo

AU - Stella, Alessandra

AU - Rizzi, Marco

AU - Maggiolo, Franco

AU - Ripamonti, Diego

AU - Suardi, Claudia

AU - Bachetti, Tiziana

AU - Rovere, Maria Teresa La

AU - Sarzi-Braga, Simona

AU - Bussotti, Maurizio

AU - Capitani, Katia

AU - Zguro, Kristina

AU - Dei, Simona

AU - Ravaglia, Sabrina

AU - Artuso, Rosangela

AU - Perrella, Antonio

AU - Bianchi, Francesco

AU - Bergomi, Paola

AU - Catena, Emanuele

AU - Colombo, Riccardo

AU - Perticaroli, Valentina

AU - Gennarelli, Massimo

AU - Magri, Chiara

AU - Magri', Carlotta

AU - Basiotto, Giorgio

AU - Zizioli, Daniela

AU - Giliani, Silvia

AU - Monti, Eugenio

AU - Focà, Emanuele

AU - Carriero, Cannio

AU - Latronico, Nicola

AU - Padovani, Alessandro

AU - Brugnoni, Duilio

PY - 2021

Y1 - 2021

N2 - A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lyso-some functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.

AB - A cytokine storm, autoimmune features and dysfunctions of myeloid cells significantly contribute to severe coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Genetic background of the host seems to be partly responsible for severe phenotype and genes related to innate immune response seem critical host determinants. The C9orf72 gene has a role in vesicular trafficking, autophagy regulation and lyso-some functions, is highly expressed in myeloid cells and is involved in immune functions, regulating the lysosomal degradation of mediators of innate immunity. A large non-coding hexanucleotide repeat expansion (HRE) in this gene is the main genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), both characterized by neuroinflammation and high systemic levels of proinflammatory cytokines, while HREs of intermediate length, although rare, are more frequent in autoimmune disorders. C9orf72 full mutation results in haploinsufficiency and intermediate HREs seem to modulate gene expression as well and impair autophagy. Herein, we sought to explore whether intermediate HREs in C9orf72 may be a risk factor for severe COVID-19. Although we found intermediate HREs in only a small portion of 240 patients with severe COVID-19 pneumonia, the magnitude of risk for requiring non-invasive or mechanical ventilation conferred by harboring intermediate repeats >10 units in at least one C9orf72 allele was more than twice respect to having shorter expansions, when adjusted for age (odds ratio (OR) 2.36; 95% confidence interval (CI) 1.04–5.37, p = 0.040). The association between intermediate repeats >10 units and more severe clinical outcome (p = 0.025) was also validated in an independent cohort of 201 SARS-CoV-2 infected patients. These data suggest that C9orf72 HREs >10 units may influence the pathogenic process driving more severe COVID-19 phenotypes.

KW - Autophagy

KW - C9orf72

KW - COVID-19

KW - Genetic risk

KW - Innate immunity

KW - Intermediate alleles

KW - SARS-CoV-2

KW - Autophagy

KW - C9orf72

KW - COVID-19

KW - Genetic risk

KW - Innate immunity

KW - Intermediate alleles

KW - SARS-CoV-2

UR - http://hdl.handle.net/10807/231807

U2 - 10.3390/ijms22136991

DO - 10.3390/ijms22136991

M3 - Article

SN - 1661-6596

VL - 22

SP - 6991-N/A

JO - International Journal of Molecular Sciences

JF - International Journal of Molecular Sciences

ER -

C9orf72 intermediate repeats confer genetic risk for severe covid-19 pneumonia independently of age

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