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| Pàgina inicial > Articles > Articles publicats > Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19 |
(University Paris Cité) (Rockefeller University) (University Paris Cité) (Helix) (Necker Hospital for Sick Children) (University Paris Cité) (Vita-Salute San Raffaele University) (University of Antioquia UdeA) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (University of São Paulo) (Institut de Ciència i Tecnologia de Barcelona. Institut de Recerca en Biomedicina) (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa) (Hospital Universitari Vall d'Hebron. Institut de Recerca) (IRCCS Neuromed) (Institut d'Investigació Biomèdica de Bellvitge) (Institut d'Investigació Biomèdica de Bellvitge) (Hospital Universitari Vall d'Hebron) (Institut d'Investigació Biomèdica de Bellvitge) (Hospital Universitari Vall d'Hebron) (Avicenne Hospital) (Amsterdam Neuroscience) (Uniformed Services University of the Health Sciences) (Lausanne University Hospital) (New York Genome Center) (CIMI-Paris) (Sorbonne Université) (KU Leuven) (The Rockefeller University) (Laboratory of Host Defenses) (The Rockefeller University) (National Institute of Allergy and Infectious Diseases (Maryland, Estats Units d'Amèrica)) (The Rockefeller University) (The Rockefeller University) (Howard Hughes Medical Institute) (The Rockefeller University) (The Rockefeller University) (The Rockefeller University)| Data: | 2023 |
| Resum: | 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. 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. 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). 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. The online version contains supplementary material available at 10. 1186/s13073-023-01173-8. |
| Ajuts: | Instituto de Salud Carlos III PI20/00876 |
| Drets: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.  |
| Llengua: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Matèria: | COVID-19 ; Immunity ; Rare variants ; Type I interferon |
| Publicat a: | Genome Medicine, Vol. 15 (april 2023) , ISSN 1756-994X |
