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Accès ouvert déclaré 2023 article

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

78Citations signalées — pas une note de qualité
139Institutions déclarées
30Pays d’affiliation déclarés

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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.

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DOI retrouvé dans Crossref DOI retrouvé ; titre concordant.

Titre Crossref
Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
Date Crossref
05/04/2023
Éditeur
Springer Science and Business Media LLC
Type
journal-article

Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude et ne compte pas comme une seconde source scientifique indépendante.

Institutions déclarées

InsermUniversité Paris CitéInstitut des Maladies Génétiques ImagineRockefeller UniversityNational Institute of Allergy and Infectious DiseasesOffice of Extramural ResearchHelix (United States)Assistance Publique – Hôpitaux de ParisVita-Salute San Raffaele UniversityIstituti di Ricovero e Cura a Carattere ScientificoIstituto di Ricovero e Cura a Carattere Scientifico San RaffaeleKarolinska InstitutetChildren's Medical CenterAl Jalila FoundationMohammed Bin Rashid University of Medicine and Health SciencesThe San Raffaele Telethon Institute for Gene TherapyShahid Beheshti University of Medical SciencesResearch Institute Hospital 12 de OctubreGobierno del Principado de AsturiasHospital Universitario Central de AsturiasUniversidad de AntioquiaKarolinska University HospitalStockholm UniversityUniversidad de La SabanaHospital La Paz Institute for Health ResearchInstituto Maimónides de Investigación Biomédica de CórdobaHospital Universitario Reina SofíaUniversity of CórdobaSorbonne UniversitéHôpital AvicenneMaladies rénales fréquentes et rares : des mécanismes moléculaires à la médecine personnaliséeUniversitat Autònoma de BarcelonaVall d'Hebron Institut de RecercaVall d'Hebron Hospital UniversitariUniversidade de São PauloLebanese UniversityInstituto de Salud Carlos IIIHospital Universitario Nuestra Señora de CandelariaUniversidad Fernando Pessoa CanariasInstituto Tecnológico y de Energías RenovablesCentro de Investigación Biomédica en RedNorthwell HealthFeinstein Institute for Medical ResearchCentre for Genomic RegulationUniversity of SharjahIstanbul UniversityBakırköy Dr.Sadi Konuk Eğitim ve Araştırma HastanesiSağlık Bilimleri ÜniversitesiIstanbul Eye HospitalNecmettin Erbakan UniversityUniversité Paris-SaclayBicêtre HospitalMasih Daneshvari HospitalUniversitat de Vic - Universitat Central de CatalunyaInstitució Catalana de Recerca i Estudis AvançatsIrsiCaixaInstitut d'Investigació en Ciències de la Salut Germans Trias i PujolUniversité Libre de BruxellesErasmus HospitalAix-Marseille UniversitéInstitut National de Recherche pour l'Agriculture, l'Alimentation et l'EnvironnementHôpital de la TimoneUniversity of Rome Tor VergataIstituto Neurologico MediterraneoBambino Gesù Children's HospitalBilkent UniversityInstitut d'Investigació Biomédica de BellvitgeCentre for Biomedical Network Research on Rare DiseasesHospital Universitario de Gran Canaria Doctor NegrínSina HospitalKU LeuvenChildren's Hospital Mansoura UniversityUniversité Sorbonne Paris NordUniversity of Management and TechnologyIRCCS Ospedale San RaffaeleHospital Universitario Infanta LeonorAmsterdam NeuroscienceAmsterdam University Medical CentersAdam Mickiewicz University in PoznańKing Saud UniversityTel Aviv UniversityTel Aviv Sourasky Medical CenterUniversity of California, Los AngelesLudwig Cancer ResearchUniversity of OxfordLudwig Cancer Researchde Duve InstituteWalloon Excellence in Lifesciences and BiotechnologyUCLouvainWashington University in St. LouisUniformed Services University of the Health SciencesSIB Swiss Institute of BioinformaticsÉcole Polytechnique Fédérale de LausanneUniversity of LausanneInstitute for Systems BiologyQueen Mary HospitalUniversity of Hong KongYale UniversityNew York Genome CenterColumbia UniversityAarhus UniversityAarhus University HospitalCharité - Universitätsmedizin BerlinCommissariat à l'Énergie Atomique et aux Énergies AlternativesCentre National de Recherche en Génomique HumaineCEA Paris-SaclayInvitae (United States)Hôpital Bichat-Claude-BernardCentre d'Immunologie et des Maladies InfectieusesInstitut Pierre Louis d‘Épidémiologie et de Santé PubliquePitié-Salpêtrière HospitalBiomarqueurs d’urgence et de réanimationNational Institutes of HealthThe University of MelbourneHoward Hughes Medical InstituteInnsbruck Medical UniversityUniversität InnsbruckGarvan Institute of Medical ResearchBC Children's HospitalPrecision Therapeutics (United States)McGill University Health CentreInstitute of Biomedical ScienceAgents infectieux, résistance et chimiothérapieUniversité de Picardie Jules VerneUniversity of Milano-BicoccaKing Saud Medical CityDasman Diabetes InstituteUniversity of California, San FranciscoUniversidad de MedellínIcahn School of Medicine at Mount SinaiShupyk National Healthcare University of UkraineStanford UniversityChildren's Healthcare of AtlantaMurdoch Children's Research InstituteBai Jerbai Wadia Hospital for ChildrenUniversity of Wisconsin–MadisonMilitary HospitalBerlin Heart (Germany)Berlin-Brandenburger Centrum für Regenerative Therapien

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Sujets associés

COVID-19 Clinical Research StudiesImmune responses and vaccinationsImmunodeficiency and Autoimmune Disorders

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