eLife (Mar 2021)
Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study
- Chiara Fallerini,
- Sergio Daga,
- Stefania Mantovani,
- Elisa Benetti,
- Nicola Picchiotti,
- Daniela Francisci,
- Francesco Paciosi,
- Elisabetta Schiaroli,
- Margherita Baldassarri,
- Francesca Fava,
- Maria Palmieri,
- Serena Ludovisi,
- Francesco Castelli,
- Eugenia Quiros-Roldan,
- Massimo Vaghi,
- Stefano Rusconi,
- Matteo Siano,
- Maria Bandini,
- Ottavia Spiga,
- Katia Capitani,
- Simone Furini,
- Francesca Mari,
- GEN-COVID Multicenter Study,
- Alessandra Renieri,
- Mario U Mondelli,
- Elisa Frullanti
Affiliations
- Chiara Fallerini
- ORCiD
- Medical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
- Sergio Daga
- ORCiD
- Medical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
- Stefania Mantovani
- ORCiD
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
- Elisa Benetti
- ORCiD
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
- Nicola Picchiotti
- ORCiD
- Department of Mathematics, University of Pavia, Pavia, Italy; University of Siena, DIISM-SAILAB, Siena, Italy
- Daniela Francisci
- Infectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Perugia, Italy; Infectious Diseases Clinic, "Santa Maria" Hospital, University of Perugia, Perugia, Italy
- Francesco Paciosi
- Infectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Perugia, Italy; Infectious Diseases Clinic, "Santa Maria" Hospital, University of Perugia, Perugia, Italy
- Elisabetta Schiaroli
- Infectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Perugia, Italy
- Margherita Baldassarri
- ORCiD
- Medical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
- Francesca Fava
- ORCiD
- Medical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
- Maria Palmieri
- ORCiD
- Medical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
- Serena Ludovisi
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Francesco Castelli
- Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy
- Eugenia Quiros-Roldan
- Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy
- Massimo Vaghi
- Chirurgia Vascolare, Ospedale Maggiore di Crema, Crema, Italy
- Stefano Rusconi
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy; III Infectious Diseases Unit, ASST-FBF-Sacco, Milan, Italy
- Matteo Siano
- Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy
- Maria Bandini
- Department of Preventive Medicine, Azienda USL Toscana Sud Est, Siena, Italy
- Ottavia Spiga
- University of Siena, DIISM-SAILAB, Siena, Italy; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
- Katia Capitani
- Medical Genetics, University of Siena, Siena, Italy; Molecular Mechanisms of Oncogenesis, ISPRO Core Research Laboratory (CRL), Firenze, Italy
- Simone Furini
- ORCiD
- Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
- Francesca Mari
- Medical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
- GEN-COVID Multicenter Study
- Medical Genetics, University of Siena, Siena, Italy
- Alessandra Renieri
- ORCiD
- Medical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy; Genetica Medica, Azienda Ospedaliero-Universitaria Senese, Siena, Italy
- Mario U Mondelli
- Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy; Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- Elisa Frullanti
- ORCiD
- Medical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
- DOI
- https://doi.org/10.7554/eLife.67569
- Journal volume & issue
-
Vol. 10
Abstract
Background: 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. Methods: 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. Results: 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. Conclusions: 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. Funding: Funded by private donors for the Host Genetics Research Project, the Intesa San Paolo for 2020 charity fund, and the Host Genetics Initiative. Clinical trial number: NCT04549831.
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