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

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

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,Abou Tayoun A,Aiuti A,Alavi Darazam I,Allende L,Alonso-Arias R,Arias A,Aytekin G,Bergman P,Bondesan S,Bryceson Y,Bustos I,Cabrera-Marante O,Carcel S,Carrera P,Casari G,Chaïbi K,Colobran R,Condino-Neto A,Covill L,Delmonte O,El Zein L,Flores C,Gregersen P,Gut M,Haerynck F,Halwani R,Hancerli S,Hammarström L,Hatipoğlu N,Karbuz A,Keles S,Kyheng C,Leon-Lopez R,Franco J,Mansouri D,Martinez-Picado J,Metin Akcan O,Migeotte I,Morange P,Morelle G,Martin-Nalda A,Novelli G,Novelli A,Ozcelik T,Palabiyik F,Pan-Hammarström Q,de Diego R,Planas-Serra L,Pleguezuelo D,Prando C,Pujol A,Reyes L,Rivière J,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,Alosaimi M,Alsohime F,Baris-Feldman H,Butte M,Constantinescu S,Cooper M,Dalgard C,Fellay J,Heath J,Lau Y,Lifton R,Maniatis T,Mogensen T,von Bernuth H,Lermine A,Vidaud M,Boland A,Deleuze J,Nussbaum R,Kahn-Kirby A,Mentre F,Tubiana S,Gorochov G,Tubach F,Hausfater P,Meyts I,Zhang S,Puel A,Notarangelo L,Boisson-Dupuis S,Su H,Boisson B,Jouanguy E,Casanova J,Zhang Q,Abel L,Cobat A

Source :

2023 Apr 5

Pmid / DOI:

37020259

Abstract

BACKGROUNDWe 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.METHODSWe 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.RESULTSNo 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) 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). 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), 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). 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).CONCLUSIONSRare 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.KEYWORDSCOVID-19, Immunity, Rare variants, Type I interferon© 2023. The Author(s).

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