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

Identificador:  imarina:9296704

Handle: https://hdl.handle.net/20.500.11797/imarina9296704

Autors:  Matuozzo, Daniela; Talouarn, Estelle; Marchal, Astrid; Zhang, Peng; 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; Alavi Darazam, Ilad; Allende, Luis M; Alonso-Arias, Rebeca; Arias, Andres Augusto; Aytekin, Gokhan; Bergman, Peter; Bondesan, Simone; Bryceson, Yenan T; 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; Hammarstroem, Lennart; Hatipoglu, Nevin; Karbuz, Adem; Keles, Sevgi; Kyheng, Christele; Leon-Lopez, Rafael; Franco, Jose Luis; Mansouri, Davood; Martinez-Picado, Javier; Metin Akcan, Ozge; Migeotte, Isabelle; Morange, Pierre-Emmanuel; Morelle, Guillaume; Martin-Nalda, Andrea; Novelli, Giuseppe; Novelli, Antonio; Ozcelik, Tayfun; Palabiyik, Figen; Pan-Hammarstroem, Qiang; de Diego, Rebeca Perez; Planas-Serra, Laura; Pleguezuelo, Daniel E; Prando, Carolina; Pujol, Aurora; Reyes, Luis Felipe; Riviere, Jacques G; Rodriguez-Gallego, Carlos; Rojas, Julian; Rovere-Querini, Patrizia; Schlueter, 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; Mani

Resum:
<jats:title>Abstract</jats:title><jats:sec> <jats:title>Background</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Methods</jats:title> <jats:p>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.</jats:p> </jats:sec><jats:sec> <jats:title>Results</jats:title> <jats:p>No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was <jats:italic>TLR7</jats:italic>, with an OR of 27.68 (95%CI 1.5–528.7, <jats:italic>P</jats:italic>?=?1.1?×?10<jats:sup>?4</jats:sup>) 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], <jats:italic>P</jats:italic>?=?2.1?×?10<jats:sup>?4</jats:sup>). This enrichment was further strengthened by (1) adding the recently reported <jats:italic>TYK2</jats:italic> and <jats:italic>TLR7</jats:italic> COVID-19 loci, particularly under a recessive model (OR?=?19.65[95%CI 2.1–2635.4], <jats:italic>P</jats:italic>?=?3.4?×?10<jats:sup>?3</jats:sup>), 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], <jats:italic>P</jats:italic>?=?7.7?×?10<jats:sup>?8</jats:sup>). 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; <jats:italic>P</jats:italic>?=?1.68?×?10<jats:sup>?5</jats:sup>).</jats:p> </jats:sec><jats:sec> <jats:title>Conclusions</jats:title> <jats:p>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.</jats:p> </jats:sec>