Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study
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- Chiara Fallerini
- Medical Genetics, University of Siena, Siena, Italy
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- Sergio Daga
- Medical Genetics, University of Siena, Siena, Italy
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- Stefania Mantovani
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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- Elisa Benetti
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
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- Nicola Picchiotti
- Department of Mathematics, University of Pavia, Pavia, Italy
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- Daniela Francisci
- Infectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Perugia, Italy
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- Francesco Paciosi
- Infectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Perugia, Italy
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- Elisabetta Schiaroli
- Infectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Perugia, Italy
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- Margherita Baldassarri
- Medical Genetics, University of Siena, Siena, Italy
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- Francesca Fava
- Medical Genetics, University of Siena, Siena, Italy
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- Maria Palmieri
- Medical Genetics, University of Siena, Siena, Italy
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- Serena Ludovisi
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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- Francesco Castelli
- Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy
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- Eugenia Quiros-Roldan
- Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy
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- Massimo Vaghi
- Chirurgia Vascolare, Ospedale Maggiore di Crema, Crema, Italy
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- Stefano Rusconi
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy
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- Matteo Siano
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy
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- Maria Bandini
- Department of Preventive Medicine, Azienda USL Toscana Sud Est, Siena, Italy
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- Ottavia Spiga
- University of Siena, DIISM-SAILAB, Siena, Italy
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- Katia Capitani
- Medical Genetics, University of Siena, Siena, Italy
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- Simone Furini
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
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- Francesca Mari
- Medical Genetics, University of Siena, Siena, Italy
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- Floriana Valentino
- Medical Genetics, University of Siena, Siena, Italy
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- Gabriella Doddato
- Medical Genetics, University of Siena, Siena, Italy
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- Annarita Giliberti
- Medical Genetics, University of Siena, Siena, Italy
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- Rossella Tita
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
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- Sara Amitrano
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
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- Mirella Bruttini
- Medical Genetics, University of Siena, Siena, Italy
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- Susanna Croci
- Medical Genetics, University of Siena, Siena, Italy
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- Ilaria Meloni
- Medical Genetics, University of Siena, Siena, Italy
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- Maria Antonietta Mencarelli
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
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- Caterina Lo Rizzo
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
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- Anna Maria Pinto
- Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
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- Laura Di Sarno
- Medical Genetics, University of Siena, Siena, Italy
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- Giada Beligni
- Medical Genetics, University of Siena, Siena, Italy
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- Andrea Tommasi
- Medical Genetics, University of Siena, Siena, Italy
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- Nicola Iuso
- Medical Genetics, University of Siena, Siena, Italy
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- Francesca Montagnani
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
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- Massimiliano Fabbiani
- Dept of Specialized and Internal Medicine, Tropical and Infectious Diseases Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy
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- Barbara Rossetti
- Dept of Specialized and Internal Medicine, Tropical and Infectious Diseases Unit, Azienda Ospedaliera Universitaria Senese, Siena, Italy
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- Giacomo Zanelli
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
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- Elena Bargagli
- Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy
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- Laura Bergantini
- Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy
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- Miriana D’Alessandro
- Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy
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- Paolo Cameli
- Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy
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- David Bennett
- Unit of Respiratory Diseases and Lung Transplantation, Department of Internal and Specialist Medicine, University of Siena, Siena, Italy
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- Federico Anedda
- Dept of Emergency and Urgency, Medicine, Surgery and Neurosciences, Unit of Intensive Care Medicine, Siena University Hospital, Siena, Italy
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- Simona Marcantonio
- Dept of Emergency and Urgency, Medicine, Surgery and Neurosciences, Unit of Intensive Care Medicine, Siena University Hospital, Siena, Italy
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- Sabino Scolletta
- Dept of Emergency and Urgency, Medicine, Surgery and Neurosciences, Unit of Intensive Care Medicine, Siena University Hospital, Siena, Italy
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- Federico Franchi
- Dept of Emergency and Urgency, Medicine, Surgery and Neurosciences, Unit of Intensive Care Medicine, Siena University Hospital, Siena, Italy
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- Maria Antonietta Mazzei
- Department of Medical, Surgical and Neuro Sciences and Radiological Sciences, Unit of Diagnostic Imaging, University of Siena, Siena, Italy
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- Susanna Guerrini
- Department of Medical, Surgical and Neuro Sciences and Radiological Sciences, Unit of Diagnostic Imaging, University of Siena, Siena, Italy
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- Edoardo Conticini
- Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy
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- Luca Cantarini
- Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy
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- Bruno Frediani
- Rheumatology Unit, Department of Medicine, Surgery and Neurosciences, University of Siena, Policlinico Le Scotte, Siena, Italy
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- Danilo Tacconi
- Department of Specialized and Internal Medicine, Infectious Diseases Unit, San Donato Hospital Arezzo, San Donato Hospital Arezzo, Arezzo, Italy
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- Chiara Spertilli
- Department of Specialized and Internal Medicine, Infectious Diseases Unit, San Donato Hospital Arezzo, San Donato Hospital Arezzo, Arezzo, Italy
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- Marco Feri
- Dept of Emergency, Anesthesia Unit, San Donato Hospital, Arezzo, Italy
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- Alice Donati
- Dept of Emergency, Anesthesia Unit, San Donato Hospital, Arezzo, Italy
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- Raffaele Scala
- Department of Specialized and Internal Medicine, Pneumology Unit and UTIP, San Donato Hospital, Arezzo, Italy
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- Luca Guidelli
- Department of Specialized and Internal Medicine, Pneumology Unit and UTIP, San Donato Hospital, Arezzo, Italy
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- Genni Spargi
- Department of Emergency, Anesthesia Unit, Misericordia Hospital, Grosseto, Italy
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- Marta Corridi
- Department of Emergency, Anesthesia Unit, Misericordia Hospital, Grosseto, Italy
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- Cesira Nencioni
- Department of Specialized and Internal Medicine, Infectious Diseases Unit, Misericordia Hospital, Grosseto, Italy
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- Leonardo Croci
- Department of Specialized and Internal Medicine, Infectious Diseases Unit, Misericordia Hospital, Grosseto, Italy
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- Gian Piero Caldarelli
- Clinical Chemical Analysis Laboratory, Misericordia Hospital, Grosseto, Italy
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- Maurizio Spagnesi
- Department of Preventive Medicine, Azienda USL Toscana Sud Est, Siena, Italy
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- Davide Romani
- Department of Preventive Medicine, Azienda USL Toscana Sud Est, Siena, Italy
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- Paolo Piacentini
- Department of Preventive Medicine, Azienda USL Toscana Sud Est, Siena, Italy
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- Elena Desanctis
- Department of Preventive Medicine, Azienda USL Toscana Sud Est, Siena, Italy
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- Silvia Cappelli
- Department of Preventive Medicine, Azienda USL Toscana Sud Est, Siena, Italy
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- Anna Canaccini
- Territorial Scientific Technician Department, Azienda USL Toscana Sud Est, Siena, Italy
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- Agnese Verzuri
- Territorial Scientific Technician Department, Azienda USL Toscana Sud Est, Siena, Italy
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- Valentina Anemoli
- Territorial Scientific Technician Department, Azienda USL Toscana Sud Est, Siena, Italy
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- Agostino Ognibene
- Clinical Chemical Analysis Laboratory, San Donato Hospital, Arezzo, Italy
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- Antonella D’Arminio Monforte
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milano, Italy
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- Federica Gaia Miraglia
- Department of Health Sciences, Clinic of Infectious Diseases, ASST Santi Paolo e Carlo, University of Milan, Milano, Italy
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- Massimo Girardis
- Department of Anesthesia and Intensive Care, University of Modena and Reggio Emilia, Modena, Italy
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- Sophie Venturelli
- Department of Anesthesia and Intensive Care, University of Modena and Reggio Emilia, Modena, Italy
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- Stefano Busani
- Department of Anesthesia and Intensive Care, University of Modena and Reggio Emilia, Modena, Italy
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- Andrea Cossarizza
- Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
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- Andrea Antinori
- HIV/AIDS Department, National Institute for Infectious Diseases, IRCCS, Lazzaro Spallanzani, Rome, Italy
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- Alessandra Vergori
- HIV/AIDS Department, National Institute for Infectious Diseases, IRCCS, Lazzaro Spallanzani, Rome, Italy
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- Arianna Emiliozzi
- HIV/AIDS Department, National Institute for Infectious Diseases, IRCCS, Lazzaro Spallanzani, Rome, Italy
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- Arianna Gabrieli
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy
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- Agostino Riva
- III Infectious Diseases Unit, ASST-FBF-Sacco, Milan, Italy
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- Pier Giorgio Scotton
- Department of Infectious Diseases, Treviso Hospital, Local Health Unit 2 Marca Trevigiana, Treviso, Italy
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- Francesca Andretta
- Department of Infectious Diseases, Treviso Hospital, Local Health Unit 2 Marca Trevigiana, Treviso, Italy
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- Sandro Panese
- Clinical Infectious Diseases, Mestre Hospital, Venezia, Italy
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- Renzo Scaggiante
- Infectious Diseases Clinic, ULSS1, Belluno, Italy
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- Francesca Gatti
- Infectious Diseases Clinic, ULSS1, Belluno, Italy
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- Saverio Giuseppe Parisi
- Department of Molecular Medicine, University of Padova, Padua, Italy
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- Stefano Baratti
- Department of Molecular Medicine, University of Padova, Padua, Italy
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- Melania Degli Antoni
- Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy
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- Matteo Della Monica
- Medical Genetics and Laboratory of Medical Genetics Unit, A.O.R.N. "Antonio Cardarelli", Naples, Italy
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- Carmelo Piscopo
- Medical Genetics and Laboratory of Medical Genetics Unit, A.O.R.N. "Antonio Cardarelli", Naples, Italy
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- Mario Capasso
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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- Roberta Russo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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- Immacolata Andolfo
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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- Achille Iolascon
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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- Giuseppe Fiorentino
- Unit of Respiratory Physiopathology, AORN dei Colli, Monaldi Hospital, Naples, Italy
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- Massimo Carella
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, San Giovanni Rotondo, Italy
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- Marco Castori
- Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, San Giovanni Rotondo, Italy
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- Giuseppe Merla
- Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Naples, Italy
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- Gabriella Maria Squeo
- Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
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- Filippo Aucella
- Department of Medical Sciences, Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, San Giovanni Rotondo, Italy
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- Pamela Raggi
- Clinical Trial Office, Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, San Giovanni Rotondo, Italy
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- Carmen Marciano
- Clinical Trial Office, Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, San Giovanni Rotondo, Italy
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- Rita Perna
- Clinical Trial Office, Fondazione IRCCS Casa Sollievo della Sofferenza Hospital, San Giovanni Rotondo, San Giovanni Rotondo, Italy
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- Matteo Bassetti
- Department of Health Sciences, University of Genova, Genova, Italy
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- Antonio Di Biagio
- Infectious Diseases Clinic, Policlinico San Martino Hospital, IRCCS for Cancer Research Genova, Genova, Italy
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- Maurizio Sanguinetti
- Microbiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Medicine, Rome, Italy
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- Luca Masucci
- Microbiology, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Catholic University of Medicine, Rome, Italy
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- Serafina Valente
- Department of Cardiovascular Diseases, University of Siena, Siena, Italy
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- Marco Mandalà
- Otolaryngology Unit, University of Siena, Siena, Italy
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- Alessia Giorli
- Otolaryngology Unit, University of Siena, Siena, Italy
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- Lorenzo Salerni
- Otolaryngology Unit, University of Siena, Siena, Italy
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- Patrizia Zucchi
- Department of Internal Medicine, ASST Valtellina e Alto Lario, Sondrio, Italy
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- Pierpaolo Parravicini
- Department of Internal Medicine, ASST Valtellina e Alto Lario, Sondrio, Italy
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- Elisabetta Menatti
- Study Coordinator Oncologia Medica e Ufficio Flussi Sondrio, Sondrio, Italy
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- Tullio Trotta
- First Aid Department, Luigi Curto Hospital, Polla, Salerno, Italy
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- Ferdinando Giannattasio
- First Aid Department, Luigi Curto Hospital, Polla, Salerno, Italy
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- Gabriella Coiro
- First Aid Department, Luigi Curto Hospital, Polla, Salerno, Italy
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- Fabio Lena
- Local Health Unit-Pharmaceutical Department of Grosseto, Toscana Sud Est Local Health Unit, Grosseto, Italy
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- Domenico A Coviello
- U.O.C. Laboratorio di Genetica Umana, IRCCS Istituto G. Gaslini, Genova, Italy
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- Cristina Mussini
- Infectious Diseases Clinics, University of Modena and Reggio Emilia, Modena, Italy
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- Giancarlo Bosio
- Department of Respiratory Diseases, Azienda Ospedaliera di Cremona, Cremona, Italy
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- Enrico Martinelli
- Department of Respiratory Diseases, Azienda Ospedaliera di Cremona, Cremona, Italy
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- Sandro Mancarella
- U.O.C. Medicina, ASST Nord Milano, Ospedale Bassini, Cinisello Balsamo, Italy
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- Luisa Tavecchia
- U.O.C. Medicina, ASST Nord Milano, Ospedale Bassini, Cinisello Balsamo, Italy
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- Marco Gori
- Université Côte d’Azur, Inria, France
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- Lia Crotti
- Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy
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- Gianfranco Parati
- Istituto Auxologico Italiano, IRCCS, Department of Cardiovascular, Neural and Metabolic Sciences, San Luca Hospital, Milan, Italy
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- Chiara Gabbi
- Independent Medical Scientist, Milan, Italy
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- Isabella Zanella
- Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy
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- Marco Rizzi
- Unit of Infectious Diseases, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy
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- Franco Maggiolo
- Unit of Infectious Diseases, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy
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- Diego Ripamonti
- Unit of Infectious Diseases, ASST Papa Giovanni XXIII Hospital, Bergamo, Italy
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- Tiziana Bachetti
- Direzione Scientifica, Istituti Clinici Scientifici Maugeri IRCCS, Pavia, Italy
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- Maria Teresa La Rovere
- Istituti Clinici Scientifici Maugeri IRCCS, Department of Cardiology, Institute of Montescano, Pavia, Italy
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- Simona Sarzi-Braga
- Istituti Clinici Scientifici Maugeri, IRCCS, Department of Cardiac Rehabilitation, Institute of Tradate (VA), Tradate, Italy
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- Maurizio Bussotti
- Istituti Clinici Scientifici Maugeri, IRCCS, Department of Cardiac Rehabilitation, Institute of Milan, Milan, Italy
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- Mario Chiariello
- Istituto per lo Studio, la Prevenzione e la Rete Oncologica (ISPRO)-Core Research Laboratory and Consiglio Nazionale delle Ricerche-Istituto di Fisiologia Clinica, Siena, Italy
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- Mary Ann Belli
- ASST Nord Milano, Ospedale Bassini, Cinisello Balsamo, Italy
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- Simona Dei
- Health Management, Azienda USL Toscana Sudest, Tuscany, Italy
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- Alessandra Renieri
- Medical Genetics, University of Siena, Siena, Italy
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- Mario U Mondelli
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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- Elisa Frullanti
- Medical Genetics, University of Siena, Siena, Italy
抄録
<jats:sec id="abs1"><jats:title>Background:</jats:title><jats:p>Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.</jats:p></jats:sec><jats:sec id="abs2"><jats:title>Methods:</jats:title><jats:p>This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60 y, 79 severe cases versus 77 control cases). We applied the LASSO Logistic Regression analysis, considering only rare variants on young male subsets with extreme phenotype, picking up TLR7 as the most important susceptibility gene.</jats:p></jats:sec><jats:sec id="abs3"><jats:title>Results:</jats:title><jats:p>Overall, we found TLR7 deleterious variants in 2.1% of severely affected males and in none of the asymptomatic participants. The functional gene expression profile analysis demonstrated a reduction in TLR7-related gene expression in patients compared with controls demonstrating an impairment in type I and II IFN responses.</jats:p></jats:sec><jats:sec id="abs4"><jats:title>Conclusions:</jats:title><jats:p>Young males with TLR7 loss-of-function variants and severe COVID-19 represent a subset of male patients contributing to disease susceptibility in up to 2% of severe COVID-19.</jats:p></jats:sec><jats:sec id="abs5"><jats:title>Funding:</jats:title><jats:p>Funded by private donors for the Host Genetics Research Project, the Intesa San Paolo for 2020 charity fund, and the Host Genetics Initiative.</jats:p></jats:sec><jats:sec id="abs6"><jats:title>Clinical trial number:</jats:title><jats:p><jats:related-object document-id="NCT04549831" document-id-type="clinical-trial-number" id="RO1" source-id="ClinicalTrials.gov" source-id-type="registry-name" source-type="clinical-trials-registry" xlink:href="https://clinicaltrials.gov/show/NCT04549831">NCT04549831</jats:related-object>.</jats:p></jats:sec>
収録刊行物
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- eLife
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eLife 10 e67569-, 2021-03-02
eLife Sciences Publications, Ltd