Stratified analyses refine association between TLR7 rare variants and severe COVID-19

Area of Science:

• Genetics
• Immunology
• Infectious Diseases

Background:

• Genetic predisposition to severe COVID-19 is under extensive research.
• The role of rare host genetic variants and their interplay with other risk factors requires further elucidation.

Purpose of the Study:

• To investigate the association between rare genetic variants in 52 candidate genes and severe COVID-19.
• To refine the understanding of Toll-like receptor 7 (TLR7) variants in severe COVID-19 pathogenesis.

Main Methods:

• Sequencing of 52 etiological genes in 1,772 severe COVID-19 cases and 5,347 controls from Spain and Italy.
• Analysis of rare deleterious TLR7 variants, incorporating functional assays and protein modeling to assess effect size.
• Examination of X-chromosomal gene associations in female-only subgroups.

Main Results:

• Rare deleterious TLR7 variants were found in 2.4% of young, otherwise healthy severe COVID-19 cases versus 0.24% of controls (OR=12.3, p=1.27×10⁻¹⁰).
• Functional assays and protein modeling increased the odds ratio for TLR7 variants to 46.5 (p=1.74×10⁻¹⁵).
• Association signals for TLR7 were observed in females, suggesting complex inheritance patterns.

Conclusions:

• Rare TLR7 variants are a significant genetic risk factor for severe COVID-19, especially in younger individuals.
• Evidence supports the involvement of interferon signaling pathway genes (TLR7, IFNAR2, IFIH1, TBK1) in severe COVID-19.
• Findings contribute to understanding the genetic architecture of severe COVID-19 and host-pathogen interactions.