e-Article
Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
Document Type
article
Author
Daniela Matuozzo; Estelle Talouarn; Astrid Marchal; Peng Zhang; Jeremy 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 Augusto Arias; Gokhan Aytekin; Peter Bergman; Simone Bondesan; Yenan T. Bryceson; Ingrid G. Bustos; Oscar Cabrera-Marante; Sheila Carcel; Paola Carrera; Giorgio Casari; Khalil Chaïbi; Roger Colobran; Antonio Condino-Neto; Laura E. Covill; Ottavia M. Delmonte; Loubna El Zein; Carlos Flores; Peter K. Gregersen; Marta Gut; Filomeen Haerynck; Rabih Halwani; Selda Hancerli; Lennart Hammarström; Nevin Hatipoğlu; Adem Karbuz; Sevgi Keles; Christèle 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-Hammarström; Rebeca Pérez de Diego; Laura Planas-Serra; Daniel E. Pleguezuelo; Carolina Prando; Aurora Pujol; Luis Felipe Reyes; Jacques G. Rivière; Carlos Rodriguez-Gallego; Julian Rojas; Patrizia Rovere-Querini; Agatha Schlüter; 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; Mohammed Faraj Alosaimi; Fahad M. Alsohime; Hagit Baris-Feldman; Manish J. Butte; Stefan N. Constantinescu; Megan A. Cooper; Clifton L. Dalgard; Jacques Fellay; James R. Heath; Yu-Lung Lau; Richard P. Lifton; Tom Maniatis; Trine H. Mogensen; Horst von Bernuth; Alban Lermine; Michel Vidaud; Anne Boland; Jean-François Deleuze; Robert Nussbaum; Amanda Kahn-Kirby; France Mentre; Sarah Tubiana; Guy Gorochov; Florence Tubach; Pierre Hausfater; 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; Isabelle Meyts; Shen-Ying Zhang; Anne Puel; Luigi D. Notarangelo; Stephanie Boisson-Dupuis; Helen C. Su; Bertrand Boisson; Emmanuelle Jouanguy; Jean-Laurent Casanova; Qian Zhang; Laurent Abel; Aurélie Cobat
Source
Genome Medicine, Vol 15, Iss 1, Pp 1-25 (2023)
Subject
Language
English
ISSN
1756-994X
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.