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

ABSTRACT: Background We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7dependent 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 identifed 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 signifcance. Under a recessive model, the most signifcant 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 infuenza 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 signifcantly 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.

• Autores: Arias Sierra, Andrés Augusto; Franco Restrepo, José Luis; Matuozzo, Daniela; Talouarn, Estelle; Marchal, Astrid; Zhang, Peng; Rojas Silva, Julían; Manry, Jeremy; Seeleuthner, Yoann; Zhang, Yu; Bolze, Alexandre; Chaldebas, Matthieu; Milisavljevic, Baptiste; Gervais, Adrian; Bastard, Paul; Asano, Takaki; Bizien, Lucy; Barzaghi, Federica; Abolhassani, Hassan; Abou Tayoun, Ahmad; Aiuti, Alessandro; Ilad, Alavi Darazam; Allende, Luis M; Alonso-Arias, Rebeca; Aytekin, Gokhan; Bergman, Peter; Bondesan, Simone; Bryceson, Tenan Y.; Bustos, Ingrid G.; Cabrera-Marante, Oscar; Carcel, Sheila; Carrera, Paola; Casari, Giorgio; Chaibi, Khalil; Colobran, Roger; Condino-Neto, Antonio; Covill, Laura E.; Delmonte, Ottavia M.; El Zein, Loubna; Flores, Carlos; Gregersen, Peter K.; Gut, Marta; Haerynck, Filomeen; Halwani, Rabih; Hancerli, Selda; Hammarström, Lennart; Hatipoglu, Nevin; Karbuz, Adem; Keles, Sevgi; Kyheng, Cristele; Leon-Lopez, Rafael; Mansouri, Davood; Martinez-Picado, Javier; Ozge, Metin Akcan; Migeotte, Isabelle; Morange, Pierre-Emmanuel; Morelle, Guillaume; Martin-Nalda, Andrea; Novelli, Giuseppe; Novelli, Antonio; Ozcelik, Tayfun; Palabiyik, Figen; Pan‑Hammarström, Qiang; Perez de Diego, Rebeca; Planas-Serra, Laura; Pleguezuelo, Daniel E.; Prando, Carolina; Pujol, Aurora; Reyes, Luis Felipe; Riviere, Jacques G.; Rodriguez-Gallego, Carlos; Rovere-Querini, Patrizia; Schlüter, Agatha; Shahrooei, Mohammad; Sobh, Ali; Soler-Palacin, Pere; Tandjaoui-Lambiotte, Yacine; Tipu, Imran; Tresoldi, Cristina; Troya, Jesus; Van de Beek, Diederik; Zatz, Mayana; Zawadzki, Pawel; Al-Muhsen, Saleh Zaid; Alosaimi, Mohammed Faraj; Alsohime, Fahad M.; Baris-Feldman, Hagit; Butte, Manish J.; Constantinescu, Stefan N.; Cooper, Megan A.; Dalgard, Clifton L.; Fellay, Jacques; Heath, James R.; Lau, Yu-Lung; Lifton, Richard P.; Maniatis, Tom; Mogensen, Trine H.; von Bernuth, Horst; Lermine, Alban; Vidaud, Michel; Boland, Anne; Deleuze, Jean‑François; Nussbaum, Robert; Kahn-Kirby, Amanda; Mentre, France; Tubiana, Sarah; Gorochov, Guy; Tubach, Florence; Hausfater, Pierre; Meyts, Isabelle; Zhang, Shen-Ying; Puel, Anne; Notarangelo, Luigi D.; Boisson-Dupuis, Stephanie; Su, Helen C.; Boisson, Bertrand; Jouanguy, Emmanuelle; Casanova, Jean-Laurent; Zhang, Qian; Abel, Laurent; Cobat, Aurelie
• Tipo de recurso: Article of investigation
• Fecha de publicación: 2023
• Institución: Universidad de Antioquia
• Repositorio: Repositorio UdeA
• Idioma: eng
• OAI Identifier: oai:bibliotecadigital.udea.edu.co:10495/38898
• Acceso en línea: https://hdl.handle.net/10495/38898
• Palabra clave: Autoanticuerpos; Autoantibodies; COVID-19; Interferón Tipo I; Interferon Type I; SARS-CoV-2; Receptor Toll-Like 3; Toll-Like Receptor 3; Receptor Toll-Like 7; Toll-Like Receptor 7; Inmunidad; Immunity; https://id.nlm.nih.gov/mesh/D001323; https://id.nlm.nih.gov/mesh/D000086382; https://id.nlm.nih.gov/mesh/D007370; https://id.nlm.nih.gov/mesh/D000086402; https://id.nlm.nih.gov/mesh/D051196; https://id.nlm.nih.gov/mesh/D051199; https://id.nlm.nih.gov/mesh/D007109
• Rights: openAccess
• License: https://creativecommons.org/licenses/by/4.0/