Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19
Abstract Background We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases.Methods We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis.Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants wasTLR7, with an OR of 27.68 (95%CI:1.5-528.7,P=1.1×10−4), in analyses restricted to 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). Adding the recently reportedTYK2COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4];P=3.4×10−3). When these 14 loci andTLR7were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0],P=4.7×10−7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9],P=0.02). Finally, the patients with pLOF or 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..
| Medienart: |
|
|---|
Preprint| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
bioRxiv.org - (2024) vom: 23. Apr. Zur Gesamtaufnahme - year:2024 |
|---|
| Sprache: |
Englisch |
|---|
| Links: |
|---|
| Themen: |
|---|
| doi: |
10.1101/2022.10.22.22281221 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
XBI037702653 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | XBI037702653 | ||
| 003 | DE-627 | ||
| 005 | 20240425104611.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 221028s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1101/2022.10.22.22281221 |2 doi | |
| 035 | |a (DE-627)XBI037702653 | ||
| 035 | |a (biorXiv)10.1101/2022.10.22.22281221 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Matuozzo, Daniela |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19 |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a Computermedien |b c |2 rdamedia | ||
| 338 | |a Online-Ressource |b cr |2 rdacarrier | ||
| 520 | |a Abstract Background We previously reported inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity in 1-5% of unvaccinated patients with life-threatening COVID-19, and auto-antibodies against type I IFN in another 15-20% of cases.Methods We report here a genome-wide rare variant burden association analysis in 3,269 unvaccinated patients with life-threatening COVID-19 (1,301 previously reported and 1,968 new patients), and 1,373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. A quarter of the patients tested had antibodies against type I IFN (234 of 928) and were excluded from the analysis.Results No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants wasTLR7, with an OR of 27.68 (95%CI:1.5-528.7,P=1.1×10−4), in analyses restricted to 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). Adding the recently reportedTYK2COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4];P=3.4×10−3). When these 14 loci andTLR7were considered, all individuals hemizygous (n=20) or homozygous (n=5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0],P=4.7×10−7), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9],P=0.02). Finally, the patients with pLOF or 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. | ||
| 650 | 4 | |a Biology |7 (dpeaa)DE-84 | |
| 650 | 4 | |a 570 |7 (dpeaa)DE-84 | |
| 700 | 1 | |a Talouarn, Estelle |e verfasserin |4 aut | |
| 700 | 1 | |a Marchal, Astrid |e verfasserin |4 aut | |
| 700 | 1 | |a Manry, Jeremy |e verfasserin |4 aut | |
| 700 | 1 | |a Seeleuthner, Yoann |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Yu |e verfasserin |4 aut | |
| 700 | 1 | |a Bolze, Alexandre |e verfasserin |4 aut | |
| 700 | 1 | |a Chaldebas, Matthieu |e verfasserin |4 aut | |
| 700 | 1 | |a Milisavljevic, Baptiste |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Peng |e verfasserin |4 aut | |
| 700 | 1 | |a Gervais, Adrian |e verfasserin |4 aut | |
| 700 | 1 | |a Bastard, Paul |e verfasserin |4 aut | |
| 700 | 1 | |a Asano, Takaki |e verfasserin |4 aut | |
| 700 | 1 | |a Bizien, Lucy |e verfasserin |4 aut | |
| 700 | 1 | |a Barzaghi, Federica |e verfasserin |4 aut | |
| 700 | 1 | |a Abolhassani, Hassan |e verfasserin |4 aut | |
| 700 | 1 | |a Tayoun, Ahmad Abou |e verfasserin |4 aut | |
| 700 | 1 | |a Aiuti, Alessandro |e verfasserin |4 aut | |
| 700 | 1 | |a Darazam, Ilad Alavi |e verfasserin |4 aut | |
| 700 | 1 | |a Allende, Luis M. |e verfasserin |4 aut | |
| 700 | 1 | |a Alonso-Arias, Rebeca |e verfasserin |4 aut | |
| 700 | 1 | |a Arias, Andrés Augusto |e verfasserin |4 aut | |
| 700 | 1 | |a Aytekin, Gokhan |e verfasserin |4 aut | |
| 700 | 1 | |a Bergman, Peter |e verfasserin |4 aut | |
| 700 | 1 | |a Bondesan, Simone |e verfasserin |4 aut | |
| 700 | 1 | |a Bryceson, Yenan T. |e verfasserin |4 aut | |
| 700 | 1 | |a Bustos, Ingrid G. |e verfasserin |4 aut | |
| 700 | 1 | |a Cabrera-Marante, Oscar |e verfasserin |4 aut | |
| 700 | 1 | |a Carcel, Sheila |e verfasserin |4 aut | |
| 700 | 1 | |a Carrera, Paola |e verfasserin |4 aut | |
| 700 | 1 | |a Casari, Giorgio |e verfasserin |4 aut | |
| 700 | 1 | |a Chaïbi, Khalil |e verfasserin |4 aut | |
| 700 | 1 | |a Colobran, Roger |e verfasserin |4 aut | |
| 700 | 1 | |a Condino-Neto, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Covill, Laura E. |e verfasserin |4 aut | |
| 700 | 1 | |a El Zein, Loubna |e verfasserin |4 aut | |
| 700 | 1 | |a Flores, Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Gregersen, Peter K. |e verfasserin |4 aut | |
| 700 | 1 | |a Gut, Marta |e verfasserin |4 aut | |
| 700 | 1 | |a Haerynck, Filomeen |e verfasserin |4 aut | |
| 700 | 1 | |a Halwani, Rabih |e verfasserin |4 aut | |
| 700 | 1 | |a Hancerli, Selda |e verfasserin |4 aut | |
| 700 | 1 | |a Hammarström, Lennart |e verfasserin |4 aut | |
| 700 | 1 | |a Hatipoğlu, Nevin |e verfasserin |4 aut | |
| 700 | 1 | |a Karbuz, Adem |e verfasserin |4 aut | |
| 700 | 1 | |a Keles, Sevgi |e verfasserin |4 aut | |
| 700 | 1 | |a Kyheng, Christèle |e verfasserin |4 aut | |
| 700 | 1 | |a Leon-Lopez, Rafael |e verfasserin |4 aut | |
| 700 | 1 | |a Franco, Jose Luis |e verfasserin |4 aut | |
| 700 | 1 | |a Mansouri, Davood |e verfasserin |4 aut | |
| 700 | 1 | |a Martinez-Picado, Javier |e verfasserin |4 aut | |
| 700 | 1 | |a Akcan, Ozge Metin |e verfasserin |4 aut | |
| 700 | 1 | |a Migeotte, Isabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Morange, Pierre-Emmanuel |e verfasserin |4 aut | |
| 700 | 1 | |a Morelle, Guillaume |e verfasserin |4 aut | |
| 700 | 1 | |a Martin-Nalda, Andrea |e verfasserin |4 aut | |
| 700 | 1 | |a Novelli, Giuseppe |e verfasserin |4 aut | |
| 700 | 1 | |a Novelli, Antonio |e verfasserin |4 aut | |
| 700 | 1 | |a Ozcelik, Tayfun |e verfasserin |4 aut | |
| 700 | 1 | |a Palabiyik, Figen |e verfasserin |4 aut | |
| 700 | 1 | |a Pan-Hammarström, Qiang |e verfasserin |4 aut | |
| 700 | 1 | |a Pérez de Diego, Rebeca |e verfasserin |4 aut | |
| 700 | 1 | |a Planas-Serra, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Pleguezuelo, Daniel E. |e verfasserin |4 aut | |
| 700 | 1 | |a Prando, Carolina |e verfasserin |4 aut | |
| 700 | 1 | |a Pujol, Aurora |e verfasserin |4 aut | |
| 700 | 1 | |a Reyes, Luis Felipe |e verfasserin |4 aut | |
| 700 | 1 | |a Rivière, Jacques G. |e verfasserin |4 aut | |
| 700 | 1 | |a Rodriguez-Gallego, Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Rojas, Julian |e verfasserin |4 aut | |
| 700 | 1 | |a Rovere-Querini, Patrizia |e verfasserin |4 aut | |
| 700 | 1 | |a Schlüter, Agatha |e verfasserin |4 aut | |
| 700 | 1 | |a Shahrooei, Mohammad |e verfasserin |4 aut | |
| 700 | 1 | |a Sobh, Ali |e verfasserin |4 aut | |
| 700 | 1 | |a Soler-Palacin, Pere |e verfasserin |4 aut | |
| 700 | 1 | |a Tandjaoui-Lambiotte, Yacine |e verfasserin |4 aut | |
| 700 | 1 | |a Tipu, Imran |e verfasserin |4 aut | |
| 700 | 1 | |a Tresoldi, Cristina |e verfasserin |4 aut | |
| 700 | 1 | |a Troya, Jesus |e verfasserin |4 aut | |
| 700 | 1 | |a van de Beek, Diederik |e verfasserin |4 aut | |
| 700 | 1 | |a Zatz, Mayana |e verfasserin |4 aut | |
| 700 | 1 | |a Zawadzki, Pawel |e verfasserin |4 aut | |
| 700 | 1 | |a Al-Muhsen, Saleh Zaid |e verfasserin |4 aut | |
| 700 | 1 | |a Baris-Feldman, Hagit |e verfasserin |4 aut | |
| 700 | 1 | |a Butte, Manish J. |e verfasserin |4 aut | |
| 700 | 1 | |a Constantinescu, Stefan N. |e verfasserin |4 aut | |
| 700 | 1 | |a Cooper, Megan A. |e verfasserin |4 aut | |
| 700 | 1 | |a Dalgard, Clifton L. |e verfasserin |4 aut | |
| 700 | 1 | |a Fellay, Jacques |e verfasserin |4 aut | |
| 700 | 1 | |a Heath, James R. |e verfasserin |4 aut | |
| 700 | 1 | |a Lau, Yu-Lung |e verfasserin |4 aut | |
| 700 | 1 | |a Lifton, Richard P. |e verfasserin |4 aut | |
| 700 | 1 | |a Maniatis, Tom |e verfasserin |4 aut | |
| 700 | 1 | |a Mogensen, Trine H. |e verfasserin |4 aut | |
| 700 | 1 | |a von Bernuth, Horst |e verfasserin |4 aut | |
| 700 | 1 | |a Lermine, Alban |e verfasserin |4 aut | |
| 700 | 1 | |a Vidaud, Michel |e verfasserin |4 aut | |
| 700 | 1 | |a Boland, Anne |e verfasserin |4 aut | |
| 700 | 1 | |a Deleuze, Jean-François |e verfasserin |4 aut | |
| 700 | 1 | |a Nussbaum, Robert |e verfasserin |4 aut | |
| 700 | 1 | |a Kahn-Kirby, Amanda |e verfasserin |4 aut | |
| 700 | 1 | |a Mentre, France |e verfasserin |4 aut | |
| 700 | 1 | |a Tubiana, Sarah |e verfasserin |4 aut | |
| 700 | 1 | |a Gorochov, Guy |e verfasserin |4 aut | |
| 700 | 1 | |a Tubach, Florence |e verfasserin |4 aut | |
| 700 | 1 | |a Hausfater, Pierre |e verfasserin |4 aut | |
| 700 | 1 | |a Meyts, Isabelle |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Shen-Ying |e verfasserin |4 aut | |
| 700 | 1 | |a Puel, Anne |e verfasserin |4 aut | |
| 700 | 1 | |a Notarangelo, Luigi D. |e verfasserin |4 aut | |
| 700 | 1 | |a Boisson-Dupuis, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Su, Helen C. |e verfasserin |4 aut | |
| 700 | 1 | |a Boisson, Bertrand |e verfasserin |4 aut | |
| 700 | 1 | |a Jouanguy, Emmanuelle |e verfasserin |4 aut | |
| 700 | 1 | |a Casanova, Jean-Laurent |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Qian |e verfasserin |4 aut | |
| 700 | 1 | |a Abel, Laurent |e verfasserin |4 aut | |
| 700 | 1 | |a Cobat, Aurélie |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t bioRxiv.org |g (2024) vom: 23. Apr. |
| 773 | 1 | 8 | |g year:2024 |g day:23 |g month:04 |
| 856 | 4 | 0 | |u https://doi.org/10.1186/s13073-023-01173-8 |x 0 |z lizenzpflichtig |3 Volltext |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1101/2022.10.22.22281221 |x 0 |z kostenfrei |3 Volltext |
| 912 | |a GBV_XBI | ||
| 951 | |a AR | ||
| 952 | |j 2024 |b 23 |c 04 | ||