1. Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
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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, Chaibi, 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, Hammarstrom, L, Hatipoglu, 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, Palabiyik, F, Pan-Hammarstrom, Q, de Diego, R, Planas-Serra, L, Pleguezuelo, D, Prando, C, Pujol, A, Reyes, L, Riviere, J, Rodriguez-Gallego, C, Rojas, J, Rovere-Querini, P, Schluter, A, Shahrooei, M, Sobh, A, Soler-Palacin, P, 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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.
- Published
- 2023