Matuozzo Daniela, Talouarn Estelle, Marchal Astrid, Manry Jeremy, Seeleuthner Yoann, Zhang Yu, Bolze Alexandre, Chaldebas Matthieu, Milisavljevic Baptiste, Zhang Peng, Gervais Adrian, Bastard Paul, Asano Takaki, Bizien Lucy, Barzaghi Federica, Abolhassani Hassan, Tayoun Ahmad Abou, Aiuti Alessandro, Darazam Ilad Alavi, Allende Luis M, Alonso-Arias Rebeca, Arias Andrés Augusto, Aytekin Gokhan, Bergman Peter, Bondesan Simone, Bryceson Yenan T, Bustos Ingrid G, Cabrera-Marante Oscar, Carcel Sheila, Carrera Paola, Casari Giorgio, Chaïbi Khalil, Colobran Roger, Condino-Neto Antonio, Covill Laura E, El Zein Loubna, Flores Carlos, Gregersen Peter K, Gut Marta, Haerynck Filomeen, Halwani Rabih, Hancerli Selda, Hammarström Lennart, Hatipoğlu Nevin, Karbuz Adem, Keles Sevgi, Kyheng Christèle, Leon-Lopez Rafael, Franco Jose Luis, Mansouri Davood, Martinez-Picado Javier, Akcan Ozge Metin, Migeotte Isabelle, Morange Pierre-Emmanuel, Morelle Guillaume, Martin-Nalda Andrea, Novelli Giuseppe, Novelli Antonio, Ozcelik Tayfun, Palabiyik Figen, Pan-Hammarström Qiang, Pérez de Diego Rebeca, Planas-Serra Laura, Pleguezuelo Daniel E, Prando Carolina, Pujol Aurora, Reyes Luis Felipe, Rivière Jacques G, Rodriguez-Gallego Carlos, Rojas Julian, Rovere-Querini Patrizia, Schlüter Agatha, Shahrooei Mohammad, Sobh Ali, Soler-Palacin Pere, Tandjaoui-Lambiotte Yacine, Tipu Imran, Tresoldi Cristina, Troya Jesus, van de Beek Diederik, Zatz Mayana, Zawadzki Pawel, Al-Muhsen Saleh Zaid, Baris-Feldman Hagit, Butte Manish J, Constantinescu Stefan N, Cooper Megan A, Dalgard Clifton L, Fellay Jacques, Heath James R, Lau Yu-Lung, Lifton Richard P, Maniatis Tom, Mogensen Trine H, von Bernuth Horst, Lermine Alban, Vidaud Michel, Boland Anne, Deleuze Jean-François, Nussbaum Robert, Kahn-Kirby Amanda, Mentre France, Tubiana Sarah, Gorochov Guy, Tubach Florence, Hausfater Pierre, Meyts Isabelle, Zhang Shen-Ying, Puel Anne, Notarangelo Luigi D, Boisson-Dupuis Stephanie, Su Helen C, Boisson Bertrand, Jouanguy Emmanuelle, Casanova Jean-Laurent, Zhang Qian, Abel Laurent, Cobat Aurélie
medRxiv. 2022 Oct 25:2022.10.22.22281221. doi: 10.1101/2022.10.22.22281221.
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.
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.
No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was , with an OR of 27.68 (95%CI:1.5-528.7, 1.1×10 ), 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], 2.1×10 ). Adding the recently reported COVID-19 locus strengthened this enrichment, particularly under a recessive model (OR=19.65 [95%CI:2.1-2635.4]; 3.4×10 ). When these 14 loci and were considered, all individuals hemizygous ( =20) or homozygous ( =5) for pLOF or bLOF variants were patients (OR=39.19 [95%CI:5.2-5037.0], =4.7×10 ), who also showed an enrichment in heterozygous variants (OR=2.36 [95%CI:1.0-5.9], =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; 1.68×10 ).
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.
我们之前报道过，在1%-5%未接种疫苗且患有危及生命的新冠肺炎患者中存在TLR3和TLR7依赖性I型干扰素（IFN）免疫的先天性缺陷，另有15%-20%的病例存在针对I型干扰素的自身抗体。
我们在此报告了一项全基因组罕见变异负担关联分析，该分析纳入了3269例未接种疫苗且患有危及生命的新冠肺炎患者（1301例先前已报道患者和1968例新患者），以及1373例未接种疫苗且感染了SARS-CoV-2但无肺炎的个体。四分之一接受检测的患者具有针对I型干扰素的抗体（928例中有234例），这些患者被排除在分析之外。
没有基因达到全基因组显著性水平。在隐性模型下，在仅限于生化功能丧失（bLOF）变异的分析中，具有风险变异的最显著基因是 ，其比值比为27.68（95%置信区间：1.5-528.7， 1.1×10 ）。我们在参与TLR3依赖性I型干扰素免疫的13个流感易感性位点的罕见预测功能丧失（pLOF）变异中重复了这种富集（比值比=3.70 [95%置信区间：1.3-8.2]， 2.1×10 ）。加上最近报道的新冠肺炎位点增强了这种富集，特别是在隐性模型下（比值比=19.65 [95%置信区间：2.1-2635.4]； 3.4×10 ）。当考虑这14个位点和 时，所有pLOF或bLOF变异的半合子（ =20）或纯合子（ =5）个体均为患者（比值比=39.19 [95%置信区间：5.2-5037.0]， =4.7×10 ），这些患者在杂合子变异中也表现出富集（比值比=2.36 [95%置信区间：1.0-5.9]， =0.02）。最后，在这十五个位点存在pLOF或bLOF变异的患者明显比其他患者年轻（平均年龄[标准差]=43.3 [20.3]岁）（56.0 [17.3]岁； 1.68×10 ）。
结论TLR3和TLR7依赖性I型干扰素免疫基因的罕见变异可能是60岁以下患者中危及生命的新冠肺炎的潜在病因，特别是在隐性遗传的情况下。
