@article{Coughlan_E-2024_181159,
title = {Stratified analyses refine association between TLR7 rare variants and severe COVID-19},
author = {Coughlan, E. and Pairo-Castineira, E. and Baillie, J. and Boos, J. and Ramakrishnan, G. and Asselta, R. and Löscher, B. and Valenti, L. and de Cid, R. and Bujanda, L. and Julià, A. and May, S. and Heggemann, J. and Albillos, A. and Banales, J. and Blay, N. and Bonfanti, P. and Buti, M. and Fernandez, J. and Marsal, S. and Prati, D. and The Spanish Italian Severe COVID-19 Sequencing Group and The GenOMICC Investigators and Schultze, J. and Riess, O. and Franke, A. and Rawlik, K. and Ellinghaus, D. and Hoischen, A. and Schmidt, A. and Ludwig, K.},
month = {jun},
year = {2024},
abstract = {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 (&lt;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 the X-chromosomal gene 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.},
volume = {5},
issue = {4},
journal = {Human Genetics and Genomics Advances},
publisher = {Elsevier},
url = {https://doi.org/10.1016/j.xhgg.2024.100323},
}
