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 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.
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.
GEN-COVIDNetwork of Italian Genomes (NIG), COVID-19 section.
Article and author information
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.
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).
- Frank L van de Veerdonk, Radboud University Medical Center, Netherlands
- Received: February 16, 2021
- Accepted: February 24, 2021
- Accepted Manuscript published: March 2, 2021 (version 1)
- Version of Record published: March 23, 2021 (version 2)
- Version of Record updated: March 25, 2021 (version 3)
© 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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