Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
Research output: Contribution to journal › Research article › Contributed › peer-review
Contributors
- Université Paris Cité
- Rockefeller University
- Helix
- Vita-Salute San Raffaele University
- Karolinska Institutet
- Tehran University of Medical Sciences
- Al Jalila Children’s Specialty Hospital
- Mohammed Bin Rashid University of Medicine and Health Sciences
- Fondazione Telethon
- Shahid Beheshti University of Medical Sciences
- Complutense University
- University of Oviedo
- Universidad de Antioquia
- Konya City Hospital
- Universidad de la Sabana
- Universidad Autónoma de Madrid
- Hospital Universitario Reina Sofía
- Hôpital Avicenne
- Sorbonne Université
- Autonomous University of Barcelona
- Universidade de São Paulo
- Lebanese University
- Institute of Technology and Renewable Energies
- CIBER - Center for Biomedical Research Network
- Hospital Universitario Nuestra Senora de Candelaria
- University of Fernando Pessoa Canarias
- Northwell Health System
- CRG - Centre for Genomic Regulation
- Jeffrey Modell Diagnosis and Research Centre
- University of Sharjah
- Istanbul University
- University of Health Sciences
- Dr. Cemil Tascioglu City Hospital
- Necmettin Erbakan University
- Université Paris-Saclay
- Imagine Institute
- Necker–Enfants Malades Hospital
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.
Details
Original language | English |
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Article number | 22 |
Pages (from-to) | 1-25 |
Number of pages | 25 |
Journal | Genome medicine |
Volume | 15 |
Issue number | 2023 |
Publication status | Published - Dec 2023 |
Peer-reviewed | Yes |
External IDs
ORCID | /0009-0003-6519-0482/work/146644426 |
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WOS | 001022167700001 |
PubMed | 37020259 |
Keywords
ASJC Scopus subject areas
Keywords
- COVID-19, Immunity, Rare variants, Type I interferon, Covid-19, Autoantibodies, Humans, Middle Aged, Interferon Type I, Toll-Like Receptor 7, Young Adult, SARS-CoV-2, Adult, Toll-Like Receptor 3/genetics