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

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  • معلومة اضافية
    • Contributors:
      Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research (C2VN); Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de Recherche pour l’Agriculture, l’Alimentation et l’Environnement (INRAE); Centre National de Recherche en Génomique Humaine (CNRGH); Institut de Biologie François JACOB (JACOB); Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Direction de Recherche Fondamentale (CEA) (DRF (CEA)); Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA); Fondation Jean Dausset - Centre d’Etudes du Polymorphisme Humain Paris (CEPH); Centre de référence, d’innovation, d’expertise et de transfert (CRefIX); Institut National de Recherche en Informatique et en Automatique (Inria)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Institut National de la Santé et de la Recherche Médicale (INSERM); Génétique Evolutive Humaine - Human Evolutionary Genetics; Institut Pasteur Paris (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité); Agents infectieux, résistance et chimiothérapie - UR UPJV 4294 (AGIR); Université de Picardie Jules Verne (UPJV)-CHU Amiens-Picardie; Centre Hospitalier Universitaire de Rennes CHU Rennes = Rennes University Hospital Pontchaillou; Institut de recherche en santé, environnement et travail (Irset); Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique EHESP (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes (Biosit : Biologie - Santé - Innovation Technologique); Immuno-Rhumatologie Moléculaire (IRM); Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM); ANR-20-CE93-0003,GENVIR,Analyse multi-omique de l'immunité anti-virale: de l'identification des circuits biologiques pertinents à la découverte de défauts monogéniques héréditaires de l'immunité chez les patients avec infections virales sévères(2020); ANR-21-COVR-0039,GenMIS-C,Recherche des Déficits immunitaires innées monogéniques prédisposant au syndrome inflammatoire multisystémique chez l'enfant.(2021); ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010); ANR-20-CO11-0001,AABIFNCOV,Bases génétiques et immunologiques des auto-anticorps contre les interférons de type I prédisposant aux formes sévères de COVID-19.(2020); ANR-21-RHUS-0008,COVIFERON,Covid-19 and interferons: from discovery to therapy(2021); ANR-11-LABX-0070,TRANSPLANTEX,Nouveaux loci d'histocompatibilité/biomarqueurs en transplantation humaine: de la découverte à l'app(2011); ANR-10-LABX-0062,IBEID,Integrative Biology of Emerging Infectious Diseases(2010); European Project: 824110,H2020-INFRAIA-2018-1,EASI-Genomics(2019); European Project: 101057100,HORIZON-HLTH-2021-DISEASE-04 ,UNDINE(2022)
    • بيانات النشر:
      CCSD
      BioMed Central
    • الموضوع:
      2023
    • Collection:
      HAL-CEA (Commissariat à l'énergie atomique et aux énergies alternatives)
    • نبذة مختصرة :
      International audience ; 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) 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). 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), 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). 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). 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.
    • Relation:
      info:eu-repo/semantics/altIdentifier/pmid/37020259; info:eu-repo/grantAgreement//824110/EU/European Advanced infraStructure for Innovative Genomics/EASI-Genomics; info:eu-repo/grantAgreement//101057100/EU/The human genetic and immunological determinants of the clinical manifestations of SARS-CoV-2 infection: Towards personalised medicine/UNDINE; PUBMED: 37020259; WOS: 001022167700001
    • الرقم المعرف:
      10.1186/s13073-023-01173-8
    • الدخول الالكتروني :
      https://amu.hal.science/hal-04425905
      https://amu.hal.science/hal-04425905v1/document
      https://amu.hal.science/hal-04425905v1/file/s13073-023-01173-8.pdf
      https://doi.org/10.1186/s13073-023-01173-8
    • Rights:
      http://creativecommons.org/licenses/by/ ; info:eu-repo/semantics/OpenAccess
    • الرقم المعرف:
      edsbas.96507A3C