{"entity": "publication", "iuid": "0901cffc6ce24877bc11b454e09a5a25", "timestamp": "2026-10-07T13:39:36.497Z", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/0901cffc6ce24877bc11b454e09a5a25.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/0901cffc6ce24877bc11b454e09a5a25"}}, "title": "Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19.", "authors": [{"family": "Matuozzo", "given": "Daniela", "initials": "D"}, {"family": "Talouarn", "given": "Estelle", "initials": "E"}, {"family": "Marchal", "given": "Astrid", "initials": "A"}, {"family": "Zhang", "given": "Peng", "initials": "P"}, {"family": "Manry", "given": "Jeremy", "initials": "J"}, {"family": "Seeleuthner", "given": "Yoann", "initials": "Y"}, {"family": "Zhang", "given": "Yu", "initials": "Y"}, {"family": "Bolze", "given": "Alexandre", "initials": "A"}, {"family": "Chaldebas", "given": "Matthieu", "initials": "M"}, {"family": "Milisavljevic", "given": "Baptiste", "initials": "B"}, {"family": "Gervais", "given": "Adrian", "initials": "A"}, {"family": "Bastard", "given": "Paul", "initials": "P"}, {"family": "Asano", "given": "Takaki", "initials": "T"}, {"family": "Bizien", "given": "Lucy", "initials": "L"}, {"family": "Barzaghi", "given": "Federica", "initials": "F"}, {"family": "Abolhassani", "given": "Hassan", "initials": "H"}, {"family": "Abou Tayoun", "given": "Ahmad", "initials": "A"}, {"family": "Aiuti", "given": "Alessandro", "initials": "A"}, {"family": "Alavi Darazam", "given": "Ilad", "initials": "I"}, {"family": "Allende", "given": "Luis M", "initials": "LM"}, {"family": "Alonso-Arias", "given": "Rebeca", "initials": "R"}, {"family": "Arias", "given": "Andr\u00e9s Augusto", "initials": "AA"}, {"family": "Aytekin", "given": "Gokhan", "initials": "G"}, {"family": "Bergman", "given": "Peter", "initials": "P"}, {"family": "Bondesan", "given": "Simone", "initials": "S"}, {"family": "Bryceson", "given": "Yenan T", "initials": "YT"}, {"family": "Bustos", "given": "Ingrid G", "initials": "IG"}, {"family": "Cabrera-Marante", "given": "Oscar", "initials": "O"}, {"family": "Carcel", "given": "Sheila", "initials": "S"}, {"family": "Carrera", "given": "Paola", "initials": "P"}, {"family": "Casari", "given": "Giorgio", "initials": "G"}, {"family": "Cha\u00efbi", "given": "Khalil", "initials": "K"}, {"family": "Colobran", "given": "Roger", "initials": "R"}, {"family": "Condino-Neto", "given": "Antonio", "initials": "A"}, {"family": "Covill", "given": "Laura E", "initials": "LE"}, {"family": "Delmonte", "given": "Ottavia M", "initials": "OM"}, {"family": "El Zein", "given": "Loubna", "initials": "L"}, {"family": "Flores", "given": "Carlos", "initials": "C"}, {"family": "Gregersen", "given": "Peter K", "initials": "PK"}, {"family": "Gut", "given": "Marta", "initials": "M"}, {"family": "Haerynck", "given": "Filomeen", "initials": "F"}, {"family": "Halwani", "given": "Rabih", "initials": "R"}, {"family": "Hancerli", "given": "Selda", "initials": "S"}, {"family": "Hammarstr\u00f6m", "given": "Lennart", "initials": "L"}, {"family": "Hatipo\u011flu", "given": "Nevin", "initials": "N"}, {"family": "Karbuz", "given": "Adem", "initials": "A"}, {"family": "Keles", "given": "Sevgi", "initials": "S"}, {"family": "Kyheng", "given": "Christ\u00e8le", "initials": "C"}, {"family": "Leon-Lopez", "given": "Rafael", "initials": "R"}, {"family": "Franco", "given": "Jose Luis", "initials": "JL"}, {"family": "Mansouri", "given": "Davood", "initials": "D"}, {"family": "Martinez-Picado", "given": "Javier", "initials": "J"}, {"family": "Metin Akcan", "given": "Ozge", "initials": "O"}, {"family": "Migeotte", "given": "Isabelle", "initials": "I"}, {"family": "Morange", "given": "Pierre-Emmanuel", "initials": "PE"}, {"family": "Morelle", "given": "Guillaume", "initials": "G"}, {"family": "Martin-Nalda", "given": "Andrea", "initials": "A"}, {"family": "Novelli", "given": "Giuseppe", "initials": "G"}, {"family": "Novelli", "given": "Antonio", "initials": "A"}, {"family": "Ozcelik", "given": "Tayfun", "initials": "T"}, {"family": "Palabiyik", "given": "Figen", "initials": "F"}, {"family": "Pan-Hammarstr\u00f6m", "given": "Qiang", "initials": "Q"}, {"family": "de Diego", "given": "Rebeca P\u00e9rez", "initials": "RP"}, {"family": "Planas-Serra", "given": "Laura", "initials": "L"}, {"family": "Pleguezuelo", "given": "Daniel E", "initials": "DE"}, {"family": "Prando", "given": "Carolina", "initials": "C"}, {"family": "Pujol", "given": "Aurora", "initials": "A"}, {"family": "Reyes", "given": "Luis Felipe", "initials": "LF"}, {"family": "Rivi\u00e8re", "given": "Jacques G", "initials": "JG"}, {"family": "Rodriguez-Gallego", "given": "Carlos", "initials": "C"}, {"family": "Rojas", "given": "Julian", "initials": "J"}, {"family": "Rovere-Querini", "given": "Patrizia", "initials": "P"}, {"family": "Schl\u00fcter", "given": "Agatha", "initials": "A"}, {"family": "Shahrooei", "given": "Mohammad", "initials": "M"}, {"family": "Sobh", "given": "Ali", "initials": "A"}, {"family": "Soler-Palacin", "given": "Pere", "initials": "P"}, {"family": "Tandjaoui-Lambiotte", "given": "Yacine", "initials": "Y"}, {"family": "Tipu", "given": "Imran", "initials": "I"}, {"family": "Tresoldi", "given": "Cristina", "initials": "C"}, {"family": "Troya", "given": "Jesus", "initials": "J"}, {"family": "van de Beek", "given": "Diederik", "initials": "D"}, {"family": "Zatz", "given": "Mayana", "initials": "M"}, {"family": "Zawadzki", "given": "Pawel", "initials": "P"}, {"family": "Al-Muhsen", "given": "Saleh Zaid", "initials": "SZ"}, {"family": "Alosaimi", "given": "Mohammed Faraj", "initials": "MF"}, {"family": "Alsohime", "given": "Fahad M", "initials": "FM"}, {"family": "Baris-Feldman", "given": "Hagit", "initials": "H"}, {"family": "Butte", "given": "Manish J", "initials": "MJ"}, {"family": "Constantinescu", "given": "Stefan N", "initials": "SN"}, {"family": "Cooper", "given": "Megan A", "initials": "MA"}, {"family": "Dalgard", "given": "Clifton L", "initials": "CL"}, {"family": "Fellay", "given": "Jacques", "initials": "J"}, {"family": "Heath", "given": "James R", "initials": "JR"}, {"family": "Lau", "given": "Yu-Lung", "initials": "YL"}, {"family": "Lifton", "given": "Richard P", "initials": "RP"}, {"family": "Maniatis", "given": "Tom", "initials": "T"}, {"family": "Mogensen", "given": "Trine H", "initials": "TH"}, {"family": "von Bernuth", "given": "Horst", "initials": "H"}, {"family": "Lermine", "given": "Alban", "initials": "A"}, {"family": "Vidaud", "given": "Michel", "initials": "M"}, {"family": "Boland", "given": "Anne", "initials": "A"}, {"family": "Deleuze", "given": "Jean-Fran\u00e7ois", "initials": "JF"}, {"family": "Nussbaum", "given": "Robert", "initials": "R"}, {"family": "Kahn-Kirby", "given": "Amanda", "initials": "A"}, {"family": "Mentre", "given": "France", "initials": "F"}, {"family": "Tubiana", "given": "Sarah", "initials": "S"}, {"family": "Gorochov", "given": "Guy", "initials": "G"}, {"family": "Tubach", "given": "Florence", "initials": "F"}, {"family": "Hausfater", "given": "Pierre", "initials": "P"}, {"family": "COVID Human Genetic Effort", "given": "", "initials": ""}, {"family": "COVIDeF Study Group", "given": "", "initials": ""}, {"family": "French COVID Cohort Study Group", "given": "", "initials": ""}, {"family": "CoV-Contact Cohort", "given": "", "initials": ""}, {"family": "COVID-STORM Clinicians", "given": "", "initials": ""}, {"family": "COVID Clinicians", "given": "", "initials": ""}, {"family": "Orchestra Working Group", "given": "", "initials": ""}, {"family": "Amsterdam UMC Covid-19 Biobank", "given": "", "initials": ""}, {"family": "NIAID-USUHS COVID Study Group", "given": "", "initials": ""}, {"family": "Meyts", "given": "Isabelle", "initials": "I"}, {"family": "Zhang", "given": "Shen-Ying", "initials": "SY"}, {"family": "Puel", "given": "Anne", "initials": "A"}, {"family": "Notarangelo", "given": "Luigi D", "initials": "LD"}, {"family": "Boisson-Dupuis", "given": "Stephanie", "initials": "S"}, {"family": "Su", "given": "Helen C", "initials": "HC"}, {"family": "Boisson", "given": "Bertrand", "initials": "B"}, {"family": "Jouanguy", "given": "Emmanuelle", "initials": "E"}, {"family": "Casanova", "given": "Jean-Laurent", "initials": "JL"}, {"family": "Zhang", "given": "Qian", "initials": "Q"}, {"family": "Abel", "given": "Laurent", "initials": "L"}, {"family": "Cobat", "given": "Aur\u00e9lie", "initials": "A", "orcid": "0000-0001-7209-6257", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/55186a4757e7417389f415061b59ab5c.json"}}], "type": "journal article", "published": "2023-04-05", "journal": {"title": "Genome Med", "issn": "1756-994X", "volume": "15", "issue": "1", "pages": "22", "issn-l": "1756-994X"}, "abstract": "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.\n\nWe 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.\n\nNo 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 \u00d7 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 \u00d7 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 \u00d7 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 \u00d7 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 \u00d7 10-5).\n\nRare 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.", "doi": "10.1186/s13073-023-01173-8", "pmid": "37020259", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC10074346"}, {"db": "pii", "key": "10.1186/s13073-023-01173-8"}, {"db": "ClinicalTrials.gov", "key": "NCT04262921"}, {"db": "ClinicalTrials.gov", "key": "NCT04259892"}, {"db": "ClinicalTrials.gov", "key": "NCT04352348"}], "notes": [], "created": "2026-10-01T08:24:00.327Z", "modified": "2026-10-01T08:24:00.392Z"}