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

Autor: Boos J; Institute of Human Genetics, University of Bonn School of Medicine and University Hospital Bonn, Bonn, Germany., van der Made CI; Department of Human Genetics, Department of Internal Medicine, Radboudumc Research Institute for Medical Innovation, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands., Ramakrishnan G; Department of Medical Biosciences, Radboud University Medical Center, Nijmegen, the Netherlands., Coughlan E; Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK; Roslin Institute, University of Edinburgh, Edinburgh, UK., Asselta R; Department of Biomedical Sciences, Humanitas University, Via Rita Levi Montalcini 4, 20090 Pieve Emanuele, Milan, Italy; IRCCS Humanitas Research Hospital - via Manzoni 56, 20089 Rozzano, Milan, Italy., Löscher BS; Institute of Clinical Molecular Biology, Kiel University and University Medical Center, Kiel, Germany., Valenti LVC; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy., de Cid R; Genomes for Life-GCAT Lab, CORE Program. Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain; Grup de Recerca en Impacte de les Malalties Cròniques i les seves Trajectòries (GRIMTra) (IGTP), Badalona, Spain., Bujanda L; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; Centre for Biomedical Network Research on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain., Julià A; Vall d'Hebron Hospital Research Institute, Barcelona, Spain., Pairo-Castineira E; Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK; Roslin Institute, University of Edinburgh, Edinburgh, UK., Baillie JK; Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK; Roslin Institute, University of Edinburgh, Edinburgh, UK., May S; Institute of Clinical Molecular Biology, Kiel University and University Medical Center, Kiel, Germany., Zametica B; Institute of Human Genetics, University of Bonn School of Medicine and University Hospital Bonn, Bonn, Germany., Heggemann J; Institute of Human Genetics, University of Bonn School of Medicine and University Hospital Bonn, Bonn, Germany., Albillos A; Centre for Biomedical Network Research on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain; Department of Gastroenterology, Hospital Universitario Ramón y Cajal, Instituto Ramón y Cajal de Investigación Sanitaria (IRYCIS), University of Alcalá, Madrid, Spain., Banales JM; Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain; Centre for Biomedical Network Research on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain; Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain., Barretina J; Genomes for Life-GCAT Lab, CORE Program. Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain., Blay N; Genomes for Life-GCAT Lab, CORE Program. Germans Trias i Pujol Research Institute (IGTP), 08916 Badalona, Spain; Grup de Recerca en Impacte de les Malalties Cròniques i les seves Trajectòries (GRIMTra) (IGTP), Badalona, Spain., Bonfanti P; Division of Infectious Diseases, Università degli Studi di Milano Bicocca, Fondazione San Gerardo dei Tintori, Monza, Italy., Buti M; Centre for Biomedical Network Research on Hepatic and Digestive Diseases (CIBEREHD), Instituto de Salud Carlos III, 28029 Madrid, Spain., Fernandez J; Hospital Clinic, University of Barcelona, Barcelona, Spain; European Foundation for the Study of Chronic Liver Failure (EF CLif), Barcelona, Spain., Marsal S; Vall d'Hebron Hospital Research Institute, Barcelona, Spain., Prati D; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy., Ronzoni L; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy., Sacchi N; IBMDR, E.O. Ospedali Galliera, Genova, Italy., Schultze JL; Systems Medicine, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) e.V., Bonn, Germany; Genomics and Immunoregulation, Life and Medical Sciences (LIMES) Institute, University of Bonn, Bonn, Germany; PRECISE Platform for Genomics and Epigenomics, Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE) e.V. and University of Bonn, Bonn, Germany., Riess O; Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany; DFG NGS Competence Center Tübingen (NCCT), University of Tübingen, Tübingen, Germany., Franke A; Institute of Clinical Molecular Biology, Kiel University and University Medical Center, Kiel, Germany., Rawlik K; Baillie Gifford Pandemic Science Hub, Centre for Inflammation Research, Institute for Regeneration and Repair, University of Edinburgh, Edinburgh, UK., Ellinghaus D; Institute of Clinical Molecular Biology, Kiel University and University Medical Center, Kiel, Germany., Hoischen A; Department of Human Genetics, Department of Internal Medicine, Radboudumc Research Institute for Medical Innovation, Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands., Schmidt A; Institute of Human Genetics, University of Bonn School of Medicine and University Hospital Bonn, Bonn, Germany., Ludwig KU; Institute of Human Genetics, University of Bonn School of Medicine and University Hospital Bonn, Bonn, Germany. Electronic address: kerstin.ludwig@uni-bonn.de.
Jazyk: angličtina
Zdroj: HGG advances [HGG Adv] 2024 Oct 10; Vol. 5 (4), pp. 100323. Date of Electronic Publication: 2024 Jun 28.
DOI: 10.1016/j.xhgg.2024.100323
Abstrakt: 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.
Competing Interests: Declaration of interests K.U.L. is a co-founder of LAMPseq Diagnostics GmbH.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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