Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
Articolo
Data di Pubblicazione:
2023
Citazione:
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.M., et al.. - In: GENOME MEDICINE. - ISSN 1756-994X. - 15:1(2023). [Epub ahead of print] [10.1186/s13073-023-01173-8]
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.
Tipologia CRIS:
1.1 Articolo in rivista
Elenco autori:
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. 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.; Chaibi, K.; Colobran, R.; Condino-Neto, A.; Covill, L. E.; Delmonte, O. M.; El Zein, L.; Flores, C.; Gregersen, P. K.; Gut, M.; Haerynck, F.; Halwani, R.; Hancerli, S.; Hammarstrom, L.; Hatipoglu, N.; Karbuz, A.; Keles, S.; Kyheng, C.; Leon-Lopez, R.; Franco, J. L.; Mansouri, D.; Martinez-Picado, J.; Metin Akcan, O.; Migeotte, I.; Morange, P. -E.; Morelle, G.; Martin-Nalda, A.; Novelli, G.; Novelli, A.; Ozcelik, T.; Palabiyik, F.; Pan-Hammarstrom, Q.; De Diego, R. P.; Planas-Serra, L.; Pleguezuelo, D. E.; Prando, C.; Pujol, A.; Reyes, L. F.; Riviere, J. G.; Rodriguez-Gallego, C.; Rojas, J.; Rovere-Querini, P.; Schluter, 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.; Al-Muhsen, S.; Al-Mulla, F.; Anderson, M. S.; Andreakos, E.; Arias, A. A.; Feldman, H. B.; Belot, A.; Biggs, C. M.; Bogunovic, D.; Bondarenko, A.; Bousfiha, A. A.; Brodin, P.; Bustamante, C. D.; Chakravorty, S.; Christodoulou, J.; Desai, M.; Drolet, B. A.; Baghdadi, J. E.; Espinosa-Padilla, S.; Franco, J. L.; Froidure, A.; Hagin, D.; Henrickson, S. E.; Hsieh, E. W. Y.; Husebye, E.; Imai, K.; Itan, Y.; Jarvis, E. D.; Karamitros, T.; Kisand, K.; Ku, C. -L.; Ling, Y.; Lucas, C. L.; Marodi, L.; Milner, J. D.; Mironska, K.; Morio, T.; Ng, L. F. P.; O'Farrelly, C.; Okada, S.; Planas, A. M.; Quintana-Murci, L.; Renia, L.; Resnick, I.; Rodriguez-Gallego, C.; Sancho-Shimizu, V.; Sediva, A.; Seppanen, M. R. J.; Shcherbina, A.; Slaby, O.; Snow, A. L.; Soler-Palacin, P.; Spaan, A. N.; Tancevski, I.; Tangye, S. G.; Ramaswamy, S.; Turvey, S. E.; Uddin, F.; Uddin, M. J.; Vinh, D. C.; Casanova, J. -L.; Casanova, J. -L.; Vacher, Y.; Gysembergh-Houal, A.; Demerville, L.; Chachoua, A.; Abad, S.; Abassi, R.; Abdellaoui, A.; Abdelmalek, A.; Abdoul, H.; Abergel, H.; Abeud, F.; Abgrall, S.; Abisror, N.; Adechian, M.; Aderdour, N.; Admane, H. F.; Adnet, F.; Afritt, S.; Agostini, H.; Aguilar, C.; Agut, S.; Aiello, T. F.; Kaci, M. A.; Oufella, H. A.; Ajeenthiravasan, G.; Alauzy, V.; Alby-Laurent, F.; Allard, L.; Alyanakian, M. -A.; Borrero, B. A.; Amam, S.; Amrouche, L.; Andronikof, M.; Anglicheau, D.; Anguel, N.; Annane, D.; Aounzou, M.; Aparicio, C.; Aratus, G.; Arlet, J. -B.; Arzoine, J.; Aslangul, E.; Assefi, M.; Aubry, A.; Audiffred, L.; Audureau, E.; Auger, C. N.; Auregan, J. -C.; Awotar, C.; Milla, S. A.; Azan, D.; Azemar, L.; Azzouguen, B.; Elrufaai, M. B.; Badsi, A.; Bakouboula, P.; Balcerowiak, C.; Balde, F.; Baldivia, E.; Bangamingo, E. -F.; Baptiste, A.; Baran-Marszak, F.; Barau, C.; Barget, N.; Baronnet, F.; Barthelemy, R.; Baudel, J. -L.; Baudry, C.; Baudry, E.; Beaugerie, L.; Belamri, A.; Belaube, N.; Belilita, R.; Bellassen, P.; Belmokhtar, R.; Beltran, I.; Benainous, R.; Benallaoua, M.; Benamouzig, R.; Benbara, A.; Benhida, J.; Benkhelouf, A.; Benlagha, J.; Benmostafa, C.; Benothmane, S.; Bentifraouine, M.; Berard, L.; Bernier, Q.; Berti, E.; Bertier, A.; Berton, L.; Bessis, S.; Beurton, A.; Bianco, C.; Bianquis, C.; Bidar, F.; Blanche, P.; Blayau, C.; Bleibtreu, A.; Blin, E.; Bloch-Queyrat, C.; Boissier, M. -C.; Bollens, D.; Bolzoni, M.; Bompard, R.; Bonnet
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