Department of Molecular Biology and Genetics

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    Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
    (BioMed Central Ltd., 2023-04-05) Matuozzo D.; Talouarn E.; Marchal A.; Zhang P.; Manry J.; Seeleuthner Y.; Zhang Y.; Bolze A.; Chaldebas M.; Milisavljevic B.; Gervais A.; Bastard P.; Asano T.; Bizien L.; Barzaghi F.; Abolhassani H.; Tayoun A.A.; Aiuti A.; Darazam I.A.; Allende L.M.; Alonso-Arias R.; Arias A.A.; Aytekin G.; Bergman P.; Bondesan S.; Bryceson Y.T.; Bustos I.G.; Cabrera-Marante O.; Carcel S.; Carrera P.; Casari G.; Chaïbi K.; Colobran R.; Condino-Neto A.; Covill L.E.; Delmonte O.M.; Zein L.E.; Flores C.; Gregersen P.K.; Gut M.; Haerynck F.; Halwani R.; Hancerli S.; Hammarström L.; Hatipoğlu N.; Karbuz A.; Keles S.; Kyheng C.; Leon-Lopez R.; Franco J.L.; Mansouri D.; Martinez-Picado J.; Akcan O.M.; Migeotte I.; Morange P.-E.; Morelle G.; Martin-Nalda A.; Novelli G.; Novelli A.; Özçelik Tayfun; Palabiyik F.; Pan-Hammarström Q.; de Diego R.P.; Planas-Serra L.; Pleguezuelo D.E.; Prando C.; Pujol A.; Reyes L.F.; Rivière J.G.; Rodriguez-Gallego C.; Rojas J.; Rovere-Querini P.; Schlüter A.; Shahrooei M.; Sobh A.; Soler-Palacin P.; Tandjaoui-Lambiotte Y.; Tipu I.; Tresoldi C.; Troya J.; van de Beek D.; Zatz M.; Zawadzki P.; Al-Muhsen S.Z.; Alosaimi M.F.; Alsohime F.M.; Baris-Feldman H.; Butte M.J.; Constantinescu S.N.; Cooper M.A.; Dalgard C.L.; Fellay J.; Heath J.R.; Lau Y.-L.; Lifton R.P.; Maniatis T.; Mogensen T.H.; von Bernuth H.; Lermine A.; Vidaud M.; Boland A.; Deleuze J.-F.; Nussbaum R.; Kahn-Kirby A.; Mentre F.; Tubiana S.; Gorochov G.; Tubach F.; Hausfater P.; Meyts I.; Zhang S.-Y.; Puel A.; Notarangelo L.D.; Boisson-Dupuis S.; Su H.C.; Boisson B.; Jouanguy E.; Casanova J.-L.; Zhang Q.; Abel L.; Cobat A.
    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 identifed 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 signifcance. Under a recessive model, the most signifcant 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 infuenza 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 signifcantly 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.