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 
Published: October 2022

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 wasTLR7, 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 reportedTYK2COVID-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 andTLR7were 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.