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


Jannik Boos, Caspar I van der Made, Gayatri Ramakrishnan, Eamon Coughlan, Rosanna Asselta, Britt-Sabina Löscher, Luca V C Valenti, Rafael de Cid, Luis Bujanda, Antonio Julià, Erola Pairo-Castineira, J Kenneth Baillie, Sandra May, Berina Zametica, Julia Heggemann, Agustín Albillos, Jesus M Banales, Jordi Barretina, Natalia Blay, Paolo Bonfanti, Maria Buti, Javier Fernandez, Sara Marsal, Daniele Prati, Luisa Ronzoni, Nicoletta Sacchi, Joachim L Schultze, Olaf Riess, Andre Franke, Konrad Rawlik, David Ellinghaus, Alexander Hoischen, Axel Schmidt, Kerstin U Ludwig

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Despite extensive global research into genetic predisposition for severe COVID-19, knowledge on the role of rare host genetic variants and their relation to other risk factors remains limited. Here, 52 genes with prior etiological evidence were sequenced in 1,772 severe COVID-19 cases and 5,347 population-based controls from Spain/Italy. Rare deleterious TLR7 variants were present in 2.4% of young (<60 years) cases with no reported clinical risk factors (n=378), compared to 0.24% of controls (odds ratio (OR)=12.3, p=1.27×10-10). Incorporation of the results of either functional assays or protein modeling led to a pronounced increase in effect size (ORmax=46.5, p=1.74×10-15). Association signals for X-chromosomal TLR7 were also detected in the female-only subgroup, suggesting the existence of additional mechanisms beyond X-linked recessive inheritance in males. Additionally, supporting evidence was generated for a contribution to severe COVID-19 of the previously implicated genes IFNAR2, IFIH1 and TBK1. Our results refine the genetic contribution of rare TLR7 variants to severe COVID-19, and strengthen evidence for the etiological relevance of genes in the interferon signaling pathway.