TY - JOUR
T1 - Stratified analyses refine association between TLR7 rare variants and severe COVID-19
AU - Spanish/Italian Severe COVID-19 Sequencing group
AU - Boos, Jannik
AU - van der Made, Caspar I
AU - Ramakrishnan, Gayatri
AU - Coughlan, Eamon
AU - Asselta, Rosanna
AU - Löscher, Britt-Sabina
AU - Valenti, Luca V C
AU - de Cid, Rafael
AU - Bujanda, Luis
AU - Julià, Antonio
AU - Pairo-Castineira, Erola
AU - Baillie, J Kenneth
AU - May, Sandra
AU - Zametica, Berina
AU - Heggemann, Julia
AU - Albillos, Agustín
AU - Banales, Jesus M
AU - Barretina, Jordi
AU - Blay, Natalia
AU - Bonfanti, Paolo
AU - Buti, Maria
AU - Fernandez, Javier
AU - Marsal, Sara
AU - Prati, Daniele
AU - Ronzoni, Luisa
AU - Sacchi, Nicoletta
AU - Schultze, Joachim L
AU - Riess, Olaf
AU - Franke, Andre
AU - Rawlik, Konrad
AU - Ellinghaus, David
AU - Hoischen, Alexander
AU - Schmidt, Axel
AU - Ludwig, Kerstin U
N1 - Copyright © 2024. Published by Elsevier Inc.
PY - 2024/10/10
Y1 - 2024/10/10
N2 - 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 (OR max = 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.
AB - 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 (OR max = 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.
KW - SARS-CoV-2
KW - burden analysis
KW - host genetics
KW - immune deficiency
KW - infection
KW - innate immunity
KW - rare variants
KW - targeted sequencing
KW - toll-like receptor 7
KW - variant collapsing analysis
U2 - 10.1016/j.xhgg.2024.100323
DO - 10.1016/j.xhgg.2024.100323
M3 - Article
C2 - 38944683
SN - 2666-2477
VL - 5
SP - 1
EP - 12
JO - Human Genetics and Genomics Advances
JF - Human Genetics and Genomics Advances
IS - 4
M1 - 100323
ER -