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

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.

• Authors: 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
• Journal: eLife (Elife) Vol. 10 (03 02 2021) ISSN: 2050-084X [Electronic] England
• PMID: 33650967 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021, Fallerini et al.

Chemical References

• TLR7 protein, human
• Toll-Like Receptor 7

Topics

• Adult
• COVID-19 (diagnosis, epidemiology, genetics)
• Case-Control Studies
• Genetic Predisposition to Disease
• HEK293 Cells
• Humans
• Italy (epidemiology)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• SARS-CoV-2 (isolation & purification)
• Severity of Illness Index
• Toll-Like Receptor 7 (genetics)