Dataset Information

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

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.

SUBMITTER: Matuozzo D

PROVIDER: S-EPMC10074346 | biostudies-literature | 2023 Apr

REPOSITORIES: biostudies-literature

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Publications

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

Matuozzo Daniela D Talouarn Estelle E Marchal Astrid A Zhang Peng P Manry Jeremy J Seeleuthner Yoann Y Zhang Yu Y Bolze Alexandre A Chaldebas Matthieu M Milisavljevic Baptiste B Gervais Adrian A Bastard Paul P Asano Takaki T Bizien Lucy L Barzaghi Federica F Abolhassani Hassan H Abou Tayoun Ahmad A Aiuti Alessandro A Alavi Darazam Ilad I Allende Luis M LM Alonso-Arias Rebeca R Arias Andrés Augusto AA Aytekin Gokhan G Bergman Peter P Bondesan Simone S Bryceson Yenan T YT Bustos Ingrid G IG Cabrera-Marante Oscar O Carcel Sheila S Carrera Paola P Casari Giorgio G Chaïbi Khalil K Colobran Roger R Condino-Neto Antonio A Covill Laura E LE Delmonte Ottavia M OM El Zein Loubna L Flores Carlos C Gregersen Peter K PK Gut Marta M Haerynck Filomeen F Halwani Rabih R Hancerli Selda S Hammarström Lennart L Hatipoğlu Nevin N Karbuz Adem A Keles Sevgi S Kyheng Christèle C Leon-Lopez Rafael R Franco Jose Luis JL Mansouri Davood D Martinez-Picado Javier J Metin Akcan Ozge O Migeotte Isabelle I Morange Pierre-Emmanuel PE Morelle Guillaume G Martin-Nalda Andrea A Novelli Giuseppe G Novelli Antonio A Ozcelik Tayfun T Palabiyik Figen F Pan-Hammarström Qiang Q de Diego Rebeca Pérez RP Planas-Serra Laura L Pleguezuelo Daniel E DE Prando Carolina C Pujol Aurora A Reyes Luis Felipe LF Rivière Jacques G JG Rodriguez-Gallego Carlos C Rojas Julian J Rovere-Querini Patrizia P Schlüter Agatha A Shahrooei Mohammad M Sobh Ali A Soler-Palacin Pere P Tandjaoui-Lambiotte Yacine Y Tipu Imran I Tresoldi Cristina C Troya Jesus J van de Beek Diederik D Zatz Mayana M Zawadzki Pawel P Al-Muhsen Saleh Zaid SZ Alosaimi Mohammed Faraj MF Alsohime Fahad M FM Baris-Feldman Hagit H Butte Manish J MJ Constantinescu Stefan N SN Cooper Megan A MA Dalgard Clifton L CL Fellay Jacques J Heath James R JR Lau Yu-Lung YL Lifton Richard P RP Maniatis Tom T Mogensen Trine H TH von Bernuth Horst H Lermine Alban A Vidaud Michel M Boland Anne A Deleuze Jean-François JF Nussbaum Robert R Kahn-Kirby Amanda A Mentre France F Tubiana Sarah S Gorochov Guy G Tubach Florence F Hausfater Pierre P Meyts Isabelle I Zhang Shen-Ying SY Puel Anne A Notarangelo Luigi D LD Boisson-Dupuis Stephanie S Su Helen C HC Boisson Bertrand B Jouanguy Emmanuelle E Casanova Jean-Laurent JL Zhang Qian Q Abel Laurent L Cobat Aurélie A

Genome medicine 20230405 1

<h4>Background</h4>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.<h4>Methods</h4>We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients wi ...[more]

PMID: 37020259

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Project description:PurposeTo investigate the association of rare predicted loss-of-function (pLoF) variants within age-related macular degeneration (AMD) risk loci and AMD sub-phenotypes.DesignCase-control study.ParticipantsParticipants of AREDS, AREDS2, and Michigan Genomics Initiative.MethodsWhole genome sequencing data were analyzed for rare pLoF variants (frequency <0.1%) in the regions of previously identified 52 independent risk variants known to be associated with AMD. Frequency of the rare pLoF variants in cases with intermediate or advanced AMD was compared with controls. Variants were assigned to the complement, extracellular matrix (ECM), lipid, cell survival, immune system, metabolism, or unknown/other pathway. Associations of rare pLoF variant pathways with AMD sub-phenotypes were analyzed using logistic and linear regression, and Cox proportional hazards models.Main outcome measuresDifferences in rare pLoF variant pathway burden and association of rare pLoF variant pathways with sub-phenotypes within the population with AMD were evaluated.ResultsRare pLoF variants were found in 298 of 1689 cases (17.6%) and 237 of 1518 controls (15.6%) (odds ratio [OR], 1.11; 95% confidence interval [CI], 0.91-1.36; P = 0.310). An enrichment of rare pLoF variants in the complement pathway in cases versus controls (OR, 2.94; 95% CI, 1.49-5.79; P = 0.002) was observed. Within cases, associations between all rare pLoF variants and choroidal neovascularization (CNV) (OR, 1.34; 95% CI, 1.04-1.73; P = 0.023), calcified drusen (OR, 1.33; 95% CI, 1.04-1.72; P = 0.025), higher scores on the AREDS Extended AMD Severity Scale (Standardized Coefficient Beta (β)=0.346 [0.086-0.605], P = 0.009), and progression to advanced disease (hazard ratio, 1.25; 95% CI, 1.01-1.55; P = 0.042) were observed. At the pathway level, there were associations between the complement pathway and geographic atrophy (GA) (OR, 2.17; 95% CI, 1.12-4.24; P = 0.023), the complement pathway and calcified drusen (OR, 3.75; 95% CI, 1.79-7.86; P < 0.001), and the ECM pathway and more severe levels in the AREDS Extended AMD Severity Scale (β = 0.62; 95% CI, 0.04-1.20; P = 0.035).ConclusionsRare pLoF variants are associated with disease progression. Variants in the complement pathway modify the clinical course of AMD and increase the risk of developing specific sub-phenotypes.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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