| Title: |
Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19. |
| Authors: |
Matuozzo, Daniela; Talouarn, Estelle; Marchal, Astrid; Manry, Jeremy; Seeleuthner, Yoann; Zhang, Yu; Bolze, Alexandre; Chaldebas, Matthieu; Milisavljevic, Baptiste; Zhang, Peng; Gervais, Adrian; Bastard, Paul; Asano, Takaki; Bizien, Lucy; Barzaghi, Federica; Abolhassani, Hassan; Tayoun, Ahmad Abou; Aiuti, Alessandro; Darazam, Ilad Alavi; Allende, Luis M.; Alonso-Arias, Rebeca; Arias, Andrés Augusto; Aytekin, Gokhan; Bergman, Peter; Bondesan, Simone; Bryceson, Yenan T.; Bustos, Ingrid G.; Cabrera-Marante, Oscar; Carcel, Sheila; Carrera, Paola; Casari, Giorgio; Chaïbi, Khalil; Colobran, Roger; Condino-Neto, Antonio; Covill, Laura E.; El Zein, Loubna; Flores, Carlos; Gregersen, Peter K.; Gut, Marta; Haerynck, Filomeen; Halwani, Rabih; Hancerli, Selda; Hammarström, Lennart; Hatipoğlu, Nevin; Karbuz, Adem; Keles, Sevgi; Kyheng, Christèle; Leon-Lopez, Rafael; Franco, Jose Luis; Mansouri, Davood; Martinez-Picado, Javier; Akcan, Ozge Metin; Migeotte, Isabelle; Morange, Pierre-Emmanuel; Morelle, Guillaume; Martin-Nalda, Andrea; Novelli, Giuseppe; Novelli, Antonio; Ozcelik, Tayfun; Palabiyik, Figen; Pan-Hammarström, Qiang; Pérez de Diego, Rebeca; Planas-Serra, Laura; Pleguezuelo, Daniel E.; Prando, Carolina; Pujol, Aurora; Reyes, Luis Felipe; Rivière, Jacques G.; Rodriguez-Gallego, Carlos; Rojas, Julian; 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; 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; COVID Human Genetic Effort; COVIDeF Study Group; French COVID Cohort Study Group; CoV-Contact Cohort; COVID-STORM Clinicians; COVID Clinicians; Orchestra Working Group; Amsterdam UMC Covid-19 Biobank; NIAID-USUHS COVID Study Group; 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, Aurélie |
| Source: |
medRxiv |
| Publication Year: |
2022 |
| Description: |
BACKGROUND: We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases. METHODS: We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis. 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 ), in analyses restricted to 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 ). Adding the recently reported TYK2 COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; P= 3.4×10 -3 ). When these 14 loci and TLR7 were considered, all individuals hemizygous ( n =20) or homozygous ( n =5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], P =4.7×10 -7 ), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], P =0.02). Finally, the patients with pLOF or 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. ; sponsorship: NIAID NIH HHS|R01 AI088364, NCATS NIH HHS|UL1 TR001866 |
| Document Type: |
report |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
info:eu-repo/grantAgreement/EC/HE/101057100; https://lirias.kuleuven.be/handle/20.500.12942/709652; https://doi.org/10.1101/2022.10.22.22281221; https://pubmed.ncbi.nlm.nih.gov/36324795 |
| DOI: |
10.1101/2022.10.22.22281221 |
| Availability: |
https://lirias.kuleuven.be/handle/20.500.12942/709652; https://hdl.handle.net/20.500.12942/709652; https://lirias.kuleuven.be/retrieve/7b21b400-2755-4403-8e62-a3b2a4f94e9c; https://doi.org/10.1101/2022.10.22.22281221; https://pubmed.ncbi.nlm.nih.gov/36324795 |
| Rights: |
info:eu-repo/semantics/openAccess ; public ; All rights reserved |
| Accession Number: |
edsbas.F59D4C75 |
| Database: |
BASE |