Skip to main navigation Skip to search Skip to main content

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

  • COVID Human Genetic Effort
  • , COVIDeF Study Group
  • , French COVID Cohort Study Group
  • , CoV-Contact Cohort
  • , COVID Clinicians
  • , NIAID-USUHS COVID Study Group
  • , Orchestra Working Group
  • , Dan A. I. Pina-Fuentes
  • , COVID-STORM Clinicians
  • , Amsterdam UMC COVID-19 Biobank
  • Pediatric Neurology, Necker Enfants Malades, University Hospital Imagine Institute, Paris, France
  • Université Paris Cité
  • Rockefeller University
  • National Institutes of Health
  • Helix, San Mateo, CA, USA
  • Université Paris 5
  • Viral Evolution and Transmission Unit, Division of Immunology, Transplantation and Infectious Diseases, IRCCS Ospedale San Raffaele, Milan, Italy
  • Karolinska Institutet
  • Tehran University of Medical Sciences
  • Department of Paediatric Gastroenterology, United Arab Emirates
  • Mohammed Bin Rashid University of Medicine and Health Sciences
  • San Raffaele Telethon Institute for Gene Therapy
  • Vita-Salute San Raffaele University
  • Shahid Beheshti University of Medical Sciences
  • Hospital Universitario 12 de Octubre
  • Hospital Universitario Central de Asturias
  • Universidad de Antioquia
  • Konya City Hospital, Konya, Turkey.
  • Division of Clinical Immunology
  • Universidad de la Sabana
  • Universidad Autónoma de Madrid
  • Hospital Universitario Reina Sofía
  • Hôpital Avicenne
  • Sorbonne Université
  • Jeffrey Modell Diagnostic and Research Center for Primary Immunodeficiencies
  • Vall d'Hebron Research Institute
  • Hospital Universitari Vall d'Hebron
  • Universidade de São Paulo
  • Lebanese University
  • Institute of Technology and Renewable Energies
  • Centro de Investigación Biomédica en Red
  • Hospital Universitario Nuestra Senora de Candelaria
  • Universidad Fernando Pessoa Canarias
  • Northwell Health System
  • Centre for Genomic Regulation
  • Jeffrey Modell Diagnosis and Research Centre
  • University of Sharjah
  • Istanbul University
  • University of Health Sciences
  • Prof.Dr.Cemil Taşcıoglu City Hospital, Istanbul, Turkey.
  • Necmettin Erbakan University
  • Université Paris-Saclay
  • National Research Institute of Tuberculosis and Lung Disease Tehran
  • Health Sciences Research Institute of the Germans Trias i Pujol Foundation
  • The University of Vic - Central University of Catalonia
  • ICREA
  • Université libre de Bruxelles
  • Département de génétique médicale, AP-HM, Hôpital d’enfants La Timone, Marseille, France
  • Aix-Marseille Université
  • University of Rome Tor Vergata
  • IRCCS Istituto Neurologico Mediterraneo Neuromed - Pozzilli (IS)
  • IRCCS Ospedale pediatrico Bambino Gesù - Roma
  • Bilkent University
  • Bellvitge Biomedical Research Institute
  • Faculdades Pequeno Príncipe, Instituto de Pesquisa Pelé Pequeno Príncipe, Curitiba, Brazil.
  • Hospital de Gran Canaria Dr. Negrin
  • Sina Medical Complex
  • KU Leuven
  • Mansoura University
  • University of Management and Technology
  • Hospital Universitario Infanta Leonor
  • Amsterdam UMC
  • Gordion Bioscience Inc
  • Adam Mickiewicz University in Poznań
  • King Saud University
  • Tel Aviv Sourasky Medical Center
  • Tel Aviv University
  • University of California at Los Angeles
  • Ludwig Institute for Cancer Research
  • Université catholique de Louvain
  • Walloon Excellence in Life Sciences and Biotechnology (WELBIO)
  • University of Oxford
  • Washington University St. Louis
  • Uniformed Services University of the Health Sciences
  • Swiss Federal Institute of Technology Lausanne
  • Swiss Institute of Bioinformatics
  • University of Lausanne
  • Institute for Systems Biology
  • The University of Hong Kong
  • Yale University
  • Columbia University
  • New York Genome Center, New York, NY, USA
  • Aarhus University
  • Charité – Universitätsmedizin Berlin
  • Laboratoire de Biologie Médicale Multisites Seqoia
  • Centre National de Recherche en Génomique Humaine, CEA-Institut de Biologie François Jacob, Evry, France
  • Invitae Corporation
  • Université Paris 7
  • Institut national de la santé et de la recherche médicale
  • Howard Hughes Medical Institute
  • Allergy and Clinical Immunology Research Unit, Department of Microbiology, Immunology and Transplantation, KU Leuven, Leuven, Belgium
  • l'Institut des Maladies Génétiques Imagine
  • Helix
  • From the Neuroimaging Research Unit, Division of Neuroscience (P.P.), and Neurology Unite (P.P.), IRCCS San Raffaele Scientific Institute, Milan, Italy; and Department of Anatomy and Neurosciences (M.M.S.), MS Center Amsterdam, Amsterdam Neuroscience, Amsterdam UMC, Vrije Universiteit Amsterdam, the Netherlands
  • Konya City Hospital
  • Karolinska University Hospital
  • VHIR
  • Hospital Vall d’Hebron
  • CIBER - Center for Biomedical Research Network
  • Health Science University
  • Prof. Dr. Cemil Tascioglu City Hospital
  • CUB Hopital Erasme
  • Département de Génétique Médicale et de Biologie Cellulaire, APHM, Hôpital d'enfants de la Timone, 13385 Marseille, France
  • Faculdades Pequeno Príncipe
  • New York Genome Center
  • Aarhus University Hospital
  • ComUE Paris-Saclay
  • Département de Génétique et Cytogénétique

Research output: Contribution to journalArticleAcademicpeer-review

39 Downloads (Pure)

Abstract

Background: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15–20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases. Methods: We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded. Results: No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5–528.7, P = 1.1 × 10−4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3–8.2], P = 2.1 × 10−4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1–2635.4], P = 3.4 × 10−3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3–8.4], P = 7.7 × 10−8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10−5). Conclusions: Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
Original languageEnglish
Article number22
Pages (from-to)22
JournalGenome medicine
Volume15
Issue number1
DOIs
Publication statusPublished - 1 Dec 2023

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

  1. SDG 3 - Good Health and Well-being
    SDG 3 Good Health and Well-being

Keywords

  • COVID-19
  • Immunity
  • Rare variants
  • Type I interferon

Fingerprint

Dive into the research topics of 'Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19'. Together they form a unique fingerprint.

Cite this