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