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Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study

  1. Chiara Fallerini
  2. Sergio Daga
  3. Stefania Mantovani
  4. Elisa Benetti
  5. Nicola Picchiotti
  6. Daniela Francisci
  7. Francesco Paciosi
  8. Elisabetta Schiaroli
  9. Margherita Baldassarri
  10. Francesca Fava
  11. Maria Palmieri
  12. Serena Ludovisi
  13. Francesco Castelli
  14. Eugenia Quiros-Roldan
  15. Massimo Vaghi
  16. Stefano Rusconi
  17. Matteo Siano
  18. Maria Bandini
  19. Ottavia Spiga
  20. Katia Capitani
  21. Simone Furini
  22. Francesca Mari
  23. GEN-COVID Multicenter Study
  24. Alessandra Renieri  Is a corresponding author
  25. Mario U Mondelli
  26. Elisa Frullanti
  1. University of Siena, Italy
  2. Fondazione IRCCS Policlinico San Matteo, Italy
  3. University of Pavia, Pavia, Italy
  4. Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Italy
  5. University of Brescia and ASST Spedali Civili Hospital, Italy
  6. Ospedale Maggiore di Crema, Italy
  7. ASST-FBF-Sacco, Italy
  8. University of Milan, Italy
  9. Azienda USL Toscana Sud Est, Italy
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Cite this article as: eLife 2021;10:e67569 doi: 10.7554/eLife.67569

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 (<60y, 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.

Conclusion: 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.

Data availability

Sequencing data have been deposited in CINECA through http://www.nig.cineca.it/, specifically, http://nigdb.cineca.it., in the COVID-19 section through http://nigdb.cineca.it./registration/login.php. There are no restrictions on data access. Only registration is needed.

The following data sets were generated
    1. Alessandra Renieri
    (2020) GEN-COVID
    Network of Italian Genomes (NIG), COVID-19 section.

Article and author information

Author details

  1. Chiara Fallerini

    Medical Genetics, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  2. Sergio Daga

    Medical Genetics, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  3. Stefania Mantovani

    Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
    Competing interests
    The authors declare that no competing interests exist.
  4. Elisa Benetti

    Med Biotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  5. Nicola Picchiotti

    Department of Mathematics, University of Pavia, Pavia, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  6. Daniela Francisci

    Infectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Perugia, Italy
    Competing interests
    The authors declare that no competing interests exist.
  7. Francesco Paciosi

    Infectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Perugia, Italy
    Competing interests
    The authors declare that no competing interests exist.
  8. Elisabetta Schiaroli

    Infectious Diseases Clinic, Department of Medicine 2, Azienda Ospedaliera di Perugia and University of Perugia, Santa Maria Hospital, Perugia, Italy
    Competing interests
    The authors declare that no competing interests exist.
  9. Margherita Baldassarri

    Medical Genetics, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  10. Francesca Fava

    Medical Genetics, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  11. Maria Palmieri

    Medical Genetics, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  12. Serena Ludovisi

    Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
    Competing interests
    The authors declare that no competing interests exist.
  13. Francesco Castelli

    Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy
    Competing interests
    The authors declare that no competing interests exist.
  14. Eugenia Quiros-Roldan

    Department of Infectious and Tropical Diseases, University of Brescia and ASST Spedali Civili Hospital, Brescia, Italy
    Competing interests
    The authors declare that no competing interests exist.
  15. Massimo Vaghi

    Vascular Surgery, Ospedale Maggiore di Crema, Crema, Italy
    Competing interests
    The authors declare that no competing interests exist.
  16. Stefano Rusconi

    III Infectious Diseases Unit, ASST-FBF-Sacco, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  17. Matteo Siano

    Department of Biomedical and Clinical Sciences Luigi Sacco, University of Milan, Milano, Italy
    Competing interests
    The authors declare that no competing interests exist.
  18. Maria Bandini

    Department of Preventive Medicine, Azienda USL Toscana Sud Est, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  19. Ottavia Spiga

    epartment of Biotechnology, Chemistry and Pharmacy, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  20. Katia Capitani

    Medical Genetics, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  21. Simone Furini

    Department of Medical Biotechnologies, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  22. Francesca Mari

    Medical Genetics, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  23. GEN-COVID Multicenter Study

    Medical Genetics, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.
  24. Alessandra Renieri

    Medical Genetics, University of Siena, Siena, Italy
    For correspondence
    alessandra.renieri@unisi.it
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0846-9220
  25. Mario U Mondelli

    Division of Infectious Diseases and Immunology, Department of Medical Sciences and Infectious Diseases, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
    Competing interests
    The authors declare that no competing interests exist.
  26. Elisa Frullanti

    Medical Genetics, University of Siena, Siena, Italy
    Competing interests
    The authors declare that no competing interests exist.

Funding

Private Donors for Host Genetics Research Project (D.L. n 18 of March 17)

  • Alessandra Renieri

Intesa San Paolo for 2020 charity fund (N.B.2020/0119)

  • Alessandra Renieri

Host Genetics Initiative (Dipartimenti di Eccellenza 2018-2020)

  • Alessandra Renieri

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: The GEN-COVID study was consistent with Institutional guidelines and approved by the University Hospital (Azienda Ospedaliero-Universitaria Senese) Ethical Review Board, Siena, Italy (Prot n. 16929, dated March 16, 2020).

Reviewing Editor

  1. Frank L van de Veerdonk, Radboud University Medical Center, Netherlands

Publication history

  1. Received: February 16, 2021
  2. Accepted: February 24, 2021
  3. Accepted Manuscript published: March 2, 2021 (version 1)
  4. Version of Record published: March 23, 2021 (version 2)
  5. Version of Record updated: March 25, 2021 (version 3)

Copyright

© 2021, Fallerini et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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