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Daniela Matuozzo; Estelle Talouarn; Astrid Marchal; Jeremy Manry; Yoann Seeleuthner; Yu Zhang; Alexandre Bolze; Matthieu Chaldebas; Baptiste Milisavljevic; Peng Zhang; Adrian Gervais; Paul Bastard; Takaki Asano; Lucy Bizien; Federica Barzaghi; Hassan Abolhassani; Ahmad Abou Tayoun; Alessandro Aiuti; Ilad Alavi Darazam; Luis Allende; Rebeca Alonso-Arias; Andres Augusto Arias; Gokhan Aytekin; Peter Bergman; Simone Bondesan; Yenan Bryceson; Ingrid Bustos; Oscar Cabrera-Marante; Sheila Carcel; Paola Carrera; Giorgio Casari; Khalil Chaibi; Roger Colobran; Antonio Condino-Neto; Laura Covill; Loubna El Zein; Carlos Flores; Peter Gregersen; Marta Gut; Filomeen Haerynck; Rabih Halwani; Selda Hancerli; Lennart Hammarstrom; Nevin Hatipoglu; Adem Karbuz; Sevgi Keles; Christele Kyheng; Rafael Leon-Lopez; Jose Luis Franco; Davood Mansouri; Javier Martinez-Picado; Ozge Metin Akcan; Isabelle Migeotte; Pierre-Emmanuel Morange; Guillaume Morelle; Andrea Martin-Nalda; Giuseppe Novelli; Antonio Novelli; Tayfun Ozcelik; Figen Palabiyik; Qiang Pan-Hammarstrom; Rebeca Perez de Diego; Laura Planas-Serra; Daniel Pleguezuelo; Carolina Prando; Aurora Pujol; Luis Felipe Reyes; Jacques Riviere; Carlos Rodriguez-Gallego; Julian Rojas; Patrizia Rovere-Querini; Agatha Schluter; Mohammad Shahrooei; Ali Sobh; Pere Soler-Palacin; Yacine Tandjaoui-Lambiotte; Imran Tipu; Cristina Tresoldi; Jesus Troya; Diederik van de Beek; Mayana Zatz; Pawel Zawadzki; Saleh Zaid Al-Muhsen; Hagit Baris-Feldman; Manish Butte; Stefan Constantinescu; Megan Cooper; Clifton Dalgard; Jacques Fellay; James Heath; Yu-Lung Lau; Richard Lifton; Tom Maniatis; Trine Mogensen; Horst von Bernuth; Alban Lermine; Michel Vidaud; Anne Boland; Jean-Francois Deleuze; Robert Nussbaum; Amanda Kahn-Kirby; France Mentre; Sarah Tubiana; Guy Gorochov; Florence Tubach; Pierre Hausfater; Isabelle Meyts; Shen-Ying Zhang; Anne Puel; Luigi Notarangelo; Stephanie Boisson-Dupuis; Helen Su; Bertrand Boisson; Emmanuelle Jouanguy; Jean-Laurent Casanova; Qian Zhang; Laurent Abel; Aurelie Cobat.
Preprint in English | medRxiv | ID: ppmedrxiv-22281221

ABSTRACT

BackgroundWe 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. MethodsWe 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. ResultsNo 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=1.1x10-4), 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=2.1x10-4). 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=3.4x10-3). 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=4.7x10-7), 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=1.68x10-5). ConclusionsRare 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.

2.
Preprint in English | bioRxiv | ID: ppbiorxiv-478564

ABSTRACT

Human immunoglobulin heavy chain (IGH) locus on chromosome 14 includes more than 40 functional copies of the variable gene (IGHV), which, together with the joining genes (IGHJ), diversity genes (IGHD), constant genes (IGHC) and immunoglobulin light chains, code for antibodies that identify and neutralize pathogenic invaders as a part of the adaptive immune system. Because of its highly repetitive sequence composition, the IGH locus has been particularly difficult to assemble or genotype through the use of standard short read sequencing technologies. Here we introduce ImmunoTyper-SR, an algorithmic method for genotype and CNV analysis of the germline IGHV genes using Illumina whole genome sequencing (WGS) data. ImmunoTyper-SR is based on a novel combinatorial optimization formulation that aims to minimize the total edit distance between reads and their assigned IGHV alleles from a given database, with constraints on the number and distribution of reads across each called allele. We have validated ImmunoTyper-SR on 12 individuals with Illumina WGS data from the 1000 Genomes Project, whose IGHV allele composition have been studied extensively through the use of long read and targeted sequencing platforms, as well as nine individuals from the NIAID COVID Consortium who have been subjected to WGS twice. We have then applied ImmunoTyper-SR on 585 samples from the NIAID COVID Consortium to investigate associations between distinct IGHV alleles and anti-type I IFN autoantibodies which have been linked to COVID-19 severity.

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