Ultra-rare RTEL1 gene variants associate with acute severity of COVID-19 and evolution to pulmonary fibrosis as a specific long COVID disorder.
COVID-19
Long COVID
Pulmonary fibrosis
RTEL1
Journal
Respiratory research
ISSN: 1465-993X
Titre abrégé: Respir Res
Pays: England
ID NLM: 101090633
Informations de publication
Date de publication:
16 Jun 2023
16 Jun 2023
Historique:
received:
14
01
2023
accepted:
22
05
2023
medline:
19
6
2023
pubmed:
17
6
2023
entrez:
16
6
2023
Statut:
epublish
Résumé
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized. A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases. Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis. RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk. Trial Registration NCT04549831 ( www. org ).
Sections du résumé
BACKGROUND
BACKGROUND
Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a novel coronavirus that caused an ongoing pandemic of a pathology termed Coronavirus Disease 19 (COVID-19). Several studies reported that both COVID-19 and RTEL1 variants are associated with shorter telomere length, but a direct association between the two is not generally acknowledged. Here we demonstrate that up to 8.6% of severe COVID-19 patients bear RTEL1 ultra-rare variants, and show how this subgroup can be recognized.
METHODS
METHODS
A cohort of 2246 SARS-CoV-2-positive subjects, collected within the GEN-COVID Multicenter study, was used in this work. Whole exome sequencing analysis was performed using the NovaSeq6000 System, and machine learning methods were used for candidate gene selection of severity. A nested study, comparing severely affected patients bearing or not variants in the selected gene, was used for the characterisation of specific clinical features connected to variants in both acute and post-acute phases.
RESULTS
RESULTS
Our GEN-COVID cohort revealed a total of 151 patients carrying at least one RTEL1 ultra-rare variant, which was selected as a specific acute severity feature. From a clinical point of view, these patients showed higher liver function indices, as well as increased CRP and inflammatory markers, such as IL-6. Moreover, compared to control subjects, they present autoimmune disorders more frequently. Finally, their decreased diffusion lung capacity for carbon monoxide after six months of COVID-19 suggests that RTEL1 variants can contribute to the development of SARS-CoV-2-elicited lung fibrosis.
CONCLUSION
CONCLUSIONS
RTEL1 ultra-rare variants can be considered as a predictive marker of COVID-19 severity, as well as a marker of pathological evolution in pulmonary fibrosis in the post-COVID phase. This notion can be used for a rapid screening in hospitalized infected people, for vaccine prioritization, and appropriate follow-up assessment for subjects at risk. Trial Registration NCT04549831 ( www.
CLINICALTRIAL
BACKGROUND
org ).
Identifiants
pubmed: 37328761
doi: 10.1186/s12931-023-02458-7
pii: 10.1186/s12931-023-02458-7
pmc: PMC10276396
doi:
Substances chimiques
DNA Helicases
EC 3.6.4.-
RTEL1 protein, human
EC 3.6.1.-
Banques de données
ClinicalTrials.gov
['NCT04549831']
Types de publication
Multicenter Study
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
158Subventions
Organisme : Azienda Ospedaliero-Universitaria Senese
ID : Bando Ricerca COVID-19 Toscana
Organisme : Intesa San Paolo 2020 charity fund
ID : N B/2020/0119 "Identificazione delle basi genetiche determinanti la variabilità clinica della risposta a COVID-19 nella popolazione italiana
Organisme : Italian Ministry of University and Research
ID : Bando FISR 2020 "Editing dell'RNA contro il SARS-CoV-2: hackerare il virus per identificare bersagli molecolari e attenuare l'infezione - HACKTHECOV"
Organisme : Istituto Buddista Italiano Soka Gakkai
ID : "PAT-COVID: Host genetics and pathogenetic mechanisms of COVID-19" (ID n. 2020-2016_RIC_3)
Organisme : EU project H2020-SC1-FA-DTS-2018-2020
ID : International consortium for integrative genomics prediction (INTERVENE) Grant Agreement No. 101016775
Investigateurs
Francesca Mari
(F)
Sergio Daga
(S)
Ilaria Meloni
(I)
Mirella Bruttini
(M)
Susanna Croci
(S)
Mirjam Lista
(M)
Debora Maffeo
(D)
Elena Pasquinelli
(E)
Viola Bianca Serio
(VB)
Enrica Antolini
(E)
Simona Letizia Basso
(SL)
Samantha Minetto
(S)
Rossella Tita
(R)
Maria Antonietta Mencarelli
(MA)
Caterina Lo Rizzo
(CL)
Anna Maria Pinto
(AM)
Francesca Ariani
(F)
Francesca Montagnani
(F)
Mario Tumbarello
(M)
Ilaria Rancan
(I)
Massimiliano Fabbiani
(M)
Paolo Cameli
(P)
David Bennett
(D)
Federico Anedda
(F)
Simona Marcantonio
(S)
Sabino Scolletta
(S)
Federico Franchi
(F)
Maria Antonietta Mazzei
(MA)
Susanna Guerrini
(S)
Edoardo Conticini
(E)
Luca Cantarini
(L)
Bruno Frediani
(B)
Danilo Tacconi
(D)
Chiara Spertilli Raffaelli
(CS)
Arianna Emiliozzi
(A)
Marco Feri
(M)
Alice Donati
(A)
Raffaele Scala
(R)
Luca Guidelli
(L)
Genni Spargi
(G)
Marta Corridi
(M)
Cesira Nencioni
(C)
Leonardo Croci
(L)
Gian Piero Caldarelli
(GP)
Davide Romani
(D)
Paolo Piacentini
(P)
Maria Bandini
(M)
Elena Desanctis
(E)
Silvia Cappelli
(S)
Anna Canaccini
(A)
Agnese Verzuri
(A)
Valentina Anemoli
(V)
Manola Pisani
(M)
Agostino Ognibene
(A)
Maria Lorubbio
(M)
Alessandro Pancrazzi
(A)
Massimo Vaghi
(M)
Antonella D 'Arminio Monforte
(AD')
Federica Gaia Miraglia
(FG)
Mario U Mondelli
(MU)
Stefania Mantovani
(S)
Raffaele Bruno
(R)
Marco Vecchia
(M)
Marcello Maffezzoni
(M)
Enrico Martinelli
(E)
Massimo Girardis
(M)
Stefano Busani
(S)
Sophie Venturelli
(S)
Andrea Cossarizza
(A)
Andrea Antinori
(A)
Alessandra Vergori
(A)
Stefano Rusconi
(S)
Matteo Siano
(M)
Arianna Gabrieli
(A)
Agostino Riva
(A)
Daniela Francisci
(D)
Elisabetta Schiaroli
(E)
Carlo Pallotto
(C)
Saverio Giuseppe Parisi
(SG)
Monica Basso
(M)
Sandro Panese
(S)
Stefano Baratti
(S)
Pier Giorgio Scotton
(PG)
Francesca Andretta
(F)
Mario Giobbia
(M)
Renzo Scaggiante
(R)
Francesca Gatti
(F)
Francesco Castelli
(F)
Eugenia Quiros-Roldan
(E)
Melania Degli Antoni
(MD)
Isabella Zanella
(I)
Matteo Della Monica
(MD)
Carmelo Piscopo
(C)
Mario Capasso
(M)
Roberta Russo
(R)
Immacolata Andolfo
(I)
Achille Iolascon
(A)
Giuseppe Fiorentino
(G)
Massimo Carella
(M)
Marco Castori
(M)
Giuseppe Merla
(G)
Gabriella Maria Squeo
(GM)
Filippo Aucella
(F)
Pamela Raggi
(P)
Rita Perna
(R)
Matteo Bassetti
(M)
Antonio Di Biagio
(A)
Maurizio Sanguinetti
(M)
Luca Masucci
(L)
Alessandra Guarnaccia
(A)
Serafina Valente
(S)
Alex Di Florio
(A)
Marco Mandalà
(M)
Alessia Giorli
(A)
Lorenzo Salerni
(L)
Patrizia Zucchi
(P)
Pierpaolo Parravicini
(P)
Elisabetta Menatti
(E)
Tullio Trotta
(T)
Ferdinando Giannattasio
(F)
Gabriella Coiro
(G)
Fabio Lena
(F)
Gianluca Lacerenza
(G)
Cristina Mussini
(C)
Luisa Tavecchia
(L)
Lia Crotti
(L)
Gianfranco Parati
(G)
Roberto Menè
(R)
Maurizio Sanarico
(M)
Marco Gori
(M)
Francesco Raimondi
(F)
Alessandra Stella
(A)
Filippo Biscarini
(F)
Tiziana Bachetti
(T)
Maria Teresa La Rovere
(MT)
Maurizio Bussotti
(M)
Serena Ludovisi
(S)
Katia Capitani
(K)
Simona Dei
(S)
Sabrina Ravaglia
(S)
Annarita Giliberti
(A)
Giulia Gori
(G)
Rosangela Artuso
(R)
Elena Andreucci
(E)
Angelica Pagliazzi
(A)
Erika Fiorentini
(E)
Antonio Perrella
(A)
Francesco Bianchi
(F)
Paola Bergomi
(P)
Emanuele Catena
(E)
Riccardo Colombo
(R)
Sauro Luchi
(S)
Giovanna Morelli
(G)
Paola Petrocelli
(P)
Sarah Iacopini
(S)
Sara Modica
(S)
Silvia Baroni
(S)
Giulia Micheli
(G)
Marco Falcone
(M)
Donato Urso
(D)
Giusy Tiseo
(G)
Tommaso Matucci
(T)
Davide Grassi
(D)
Claudio Ferri
(C)
Franco Marinangeli
(F)
Francesco Brancati
(F)
Antonella Vincenti
(A)
Valentina Borgo
(V)
Stefania Lombardi
(S)
Mirco Lenzi
(M)
Massimo Antonio Di Pietro
(MA)
Francesca Vichi
(F)
Benedetta Romanin
(B)
Letizia Attala
(L)
Cecilia Costa
(C)
Andrea Gabbuti
(A)
Alessio Bellucci
(A)
Marta Colaneri
(M)
Patrizia Casprini
(P)
Cristoforo Pomara
(C)
Massimiliano Esposito
(M)
Roberto Leoncini
(R)
Michele Cirianni
(M)
Lucrezia Galasso
(L)
Marco Antonio Bellini
(MA)
Chiara Gabbi
(C)
Nicola Picchiotti
(N)
Simone Furini
(S)
Informations de copyright
© 2023. The Author(s).
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