Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study
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 p...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-03-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/67569 |
| _version_ | 1811201695037784064 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Chiara Fallerini |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:26:00Z |
| format | Article |
| id | doaj.art-aef3d8ed1dba4f11895dca58e52e7e30 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:26:00Z |
| publishDate | 2021-03-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-aef3d8ed1dba4f11895dca58e52e7e302022-12-22T03:52:00ZengeLife Sciences Publications LtdeLife2050-084X2021-03-011010.7554/eLife.67569Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control studyChiara Fallerini0https://orcid.org/0000-0002-7386-3224Sergio Daga1https://orcid.org/0000-0002-6419-9456Stefania Mantovani2https://orcid.org/0000-0002-5885-2842Elisa Benetti3https://orcid.org/0000-0002-0819-604XNicola Picchiotti4https://orcid.org/0000-0003-3454-7250Daniela Francisci5Francesco Paciosi6Elisabetta Schiaroli7Margherita Baldassarri8https://orcid.org/0000-0002-0391-1980Francesca Fava9https://orcid.org/0000-0002-4363-2353Maria Palmieri10https://orcid.org/0000-0003-3014-1552Serena Ludovisi11Francesco Castelli12Eugenia Quiros-Roldan13Massimo Vaghi14Stefano Rusconi15Matteo Siano16Maria Bandini17Ottavia Spiga18Katia Capitani19Simone Furini20https://orcid.org/0000-0002-1099-8279Francesca Mari21GEN-COVID Multicenter Study22Alessandra Renieri23https://orcid.org/0000-0002-0846-9220Mario U Mondelli24Elisa Frullanti25https://orcid.org/0000-0001-5634-031XMedical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyMedical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyDivision of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, ItalyMed Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyDepartment of Mathematics, University of Pavia, Pavia, Italy; University of Siena, DIISM-SAILAB, Siena, ItalyInfectious 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, ItalyInfectious 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, ItalyInfectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Perugia, ItalyMedical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyMedical 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, ItalyMedical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyDivision 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, ItalyDepartment of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, ItalyDepartment of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, ItalyChirurgia Vascolare, Ospedale Maggiore di Crema, Crema, ItalyDepartment of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, Italy; III Infectious Diseases Unit, ASST-FBF-Sacco, Milan, ItalyDepartment of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milan, ItalyDepartment of Preventive Medicine, Azienda USL Toscana Sud Est, Siena, ItalyUniversity of Siena, DIISM-SAILAB, Siena, Italy; Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, ItalyMedical Genetics, University of Siena, Siena, Italy; Molecular Mechanisms of Oncogenesis, ISPRO Core Research Laboratory (CRL), Firenze, ItalyMed Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyMedical 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, ItalyMedical Genetics, University of Siena, Siena, ItalyMedical 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, ItalyDivision 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, ItalyMedical Genetics, University of Siena, Siena, Italy; Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, ItalyBackground: 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.https://elifesciences.org/articles/67569TLR7COVID-19LASSO Logistic Regression Analysis |
| spellingShingle | 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 Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study eLife TLR7 COVID-19 LASSO Logistic Regression Analysis |
| title | Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study |
| title_full | Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study |
| title_fullStr | Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study |
| title_full_unstemmed | Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study |
| title_short | Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study |
| title_sort | association of toll like receptor 7 variants with life threatening covid 19 disease in males findings from a nested case control study |
| topic | TLR7 COVID-19 LASSO Logistic Regression Analysis |
| url | https://elifesciences.org/articles/67569 |
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