Genome Medicine (Apr 2023)

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

  • 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

DOI
https://doi.org/10.1186/s13073-023-01173-8
Journal volume & issue
Vol. 15, no. 1
pp. 1 – 25

Abstract

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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.

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