Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
Daniela Matuozzo, Estelle Talouarn, Astrid Marchal, Peng Zhang, Jérémy Manry, Yoann Seeleuthner, Yu Zhang, Alexandre Bolze, Matthieu Chaldebas, Baptiste Milisavljevic, Adrian Gervais, Paul Bastard, Takaki Asano, Lucy Bizien, Federica Barzaghi, Hassan Abolhassani, Ahmad Abou Tayoun, Alessandro Aiuti, Ilad Alavi Darazam, Luis M. Allende, Rebeca Alonso‐Arias, Andrés A. Arias, Gökhan Aytekіn, Peter Bergman, Simone Bondesan, Yenan T. Bryceson, Ingrid G. Bustos, Óscar Cabrera-Marante, Sheila Cárcel, Paola Carrera, Giorgio Casari, Khalil Chaïbi, Roger Colobrán, Antônio Condino‐Neto, Laura Covill, Ottavia M. Delmonte, Loubna El Zein, Carlos Flores, Peter K. Gregersen, Marta Gut, Filomeen Haerynck, Rabih Halwani, Selda Hançerli, Lennart Hammarström, Nevin Hatipoğlu, Adem Karbuz, Sevgi Keleş, Christèle Kyheng, Rafael León‐López, José Luis Franco, Davood Mansouri, Javier Martínez‐Picado, Özge Metin Akcan, Isabelle Migeotte, Pierre‐Emmanuel Morange, Guillaume Morelle, Andrea Martín-Nalda, Giuseppe Novelli, Antonio Novelli, Tayfun Özçelık, Figen Palabıyık, Qiang Pan‐Hammarström, Rebeca Pérez de Diego, Laura Planas‐Serra, Daniel E. Pleguezuelo, Carolina Prando, Aurora Pujol, Luis Felipe Reyes, Jacques G. Rivière, Carlos Rodríguez‐Gallego, Julián Rojas, Patrizia Rovere–Querini, Agatha Schlüter, Mohammad Shahrooei, Ali Sobh, Pere Soler‐Palacín, Yacine Tandjaoui-Lambiotte, Imran Tipu, Cristina Tresoldi, Jesús Troya, Diederik van de Beek, Mayana Zatz, Paweł Zawadzki, Saleh Zaid Al-Muhsen, Mohammed F. Alosaimi, Fahad Alsohime, Hagit Baris Feldman, Manish J. Butte, Stefan N. Constantinescu, Megan A. Cooper, Clifton L. Dalgard, Jacques Fellay, James R. Heath, YL Lau, Richard P. Lifton, Tom Maniatis, Trine H. Mogensen, Horst von Bernuth, Alban Lermine, Michel Vidaud
Abstract
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.