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. 2023 Apr 5;15(1):22.
doi: 10.1186/s13073-023-01173-8.

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

Daniela Matuozzo  1   2 , Estelle Talouarn  1   2 , Astrid Marchal  1   2 , Peng Zhang  3 , Jeremy Manry  1   2 , Yoann Seeleuthner  1   2 , Yu Zhang  4 , Alexandre Bolze  5 , Matthieu Chaldebas  3 , Baptiste Milisavljevic  3 , Adrian Gervais  1   2 , Paul Bastard  1   2   3   6 , Takaki Asano  3 , Lucy Bizien  1   2 , Federica Barzaghi  7 , Hassan Abolhassani  8   9 , Ahmad Abou Tayoun  10   11 , Alessandro Aiuti  12   13 , Ilad Alavi Darazam  14   15 , Luis M Allende  16 , Rebeca Alonso-Arias  17 , Andrés Augusto Arias  3   18   19 , Gokhan Aytekin  20 , Peter Bergman  21   22 , Simone Bondesan  23 , Yenan T Bryceson  24 , Ingrid G Bustos  25 , Oscar Cabrera-Marante  26 , Sheila Carcel  27 , Paola Carrera  23 , Giorgio Casari  28   29 , Khalil Chaïbi  30   31 , Roger Colobran  32   33   34 , Antonio Condino-Neto  35 , Laura E Covill  24 , Ottavia M Delmonte  4 , Loubna El Zein  36 , Carlos Flores  37   38   39   40 , Peter K Gregersen  41 , Marta Gut  42 , Filomeen Haerynck  43 , Rabih Halwani  44 , Selda Hancerli  45 , Lennart Hammarström  8 , Nevin Hatipoğlu  46 , Adem Karbuz  47 , Sevgi Keles  48 , Christèle Kyheng  49 , Rafael Leon-Lopez  27 , Jose Luis Franco  50 , Davood Mansouri  51   52   53 , Javier Martinez-Picado  54   55   56   57   58 , Ozge Metin Akcan  48 , Isabelle Migeotte  59 , Pierre-Emmanuel Morange  60   61 , Guillaume Morelle  49 , Andrea Martin-Nalda  32   62   63 , Giuseppe Novelli  64   65 , Antonio Novelli  66 , Tayfun Ozcelik  67 , Figen Palabiyik  46 , Qiang Pan-Hammarström  8 , Rebeca Pérez de Diego  68 , Laura Planas-Serra  69   70 , Daniel E Pleguezuelo  16 , Carolina Prando  71 , Aurora Pujol  57   69   70 , Luis Felipe Reyes  25 , Jacques G Rivière  32   62   63 , Carlos Rodriguez-Gallego  72   73 , Julian Rojas  50 , Patrizia Rovere-Querini  13   74 , Agatha Schlüter  69   70 , Mohammad Shahrooei  75   76 , Ali Sobh  77 , Pere Soler-Palacin  32   62   63 , Yacine Tandjaoui-Lambiotte  78 , Imran Tipu  79 , Cristina Tresoldi  80 , Jesus Troya  81 , Diederik van de Beek  82 , Mayana Zatz  83 , Pawel Zawadzki  84   85 , Saleh Zaid Al-Muhsen  86 , Mohammed Faraj Alosaimi  86 , Fahad M Alsohime  86 , Hagit Baris-Feldman  87   88 , Manish J Butte  89 , Stefan N Constantinescu  90   91   92   93 , Megan A Cooper  94 , Clifton L Dalgard  95   96 , Jacques Fellay  97   98   99 , James R Heath  100 , Yu-Lung Lau  101 , Richard P Lifton  102   103   104 , Tom Maniatis  105   106 , Trine H Mogensen  107   108 , Horst von Bernuth  109 , Alban Lermine  110 , Michel Vidaud  110 , Anne Boland  111 , Jean-François Deleuze  111 , Robert Nussbaum  112 , Amanda Kahn-Kirby  112 , France Mentre  113 , Sarah Tubiana  114 , Guy Gorochov  115 , Florence Tubach  116 , Pierre Hausfater  117   118 ; COVID Human Genetic Effort; COVIDeF Study Group; French COVID Cohort Study Group; CoV-Contact Cohort; COVID-STORM Clinicians; COVID Clinicians; Orchestra Working Group; Amsterdam UMC Covid-19 Biobank; NIAID-USUHS COVID Study Group; Isabelle Meyts  119 , Shen-Ying Zhang  1   2   3 , Anne Puel  1   2   3 , Luigi D Notarangelo  120 , Stephanie Boisson-Dupuis  1   2   3 , Helen C Su  4 , Bertrand Boisson  1   2   3 , Emmanuelle Jouanguy  1   2   3 , Jean-Laurent Casanova #  121   122   123   124 , Qian Zhang #  1   2   3 , Laurent Abel #  1   2   3 , Aurélie Cobat #  125   126   127
Collaborators, Affiliations

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

Daniela Matuozzo et al. Genome Med. .

Erratum in

  • Correction: 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, Tayoun AA, Aiuti A, Darazam IA, Allende LM, Alonso-Arias R, Arias AA, Aytekin G, Bergman P, Bondesan S, Bryceson YT, Bustos IG, Cabrera-Marante O, Carcel S, Carrera P, Casari G, Chaïbi K, Colobran R, Condino-Neto A, Covill LE, Delmonte OM, Zein LE, Flores C, Gregersen PK, Gut M, Haerynck F, Halwani R, Hancerli S, Hammarström L, Hatipoğlu N, Karbuz A, Keles S, Kyheng C, Leon-Lopez R, Franco JL, Mansouri D, Martinez-Picado J, Akcan OM, Migeotte I, Morange PE, Morelle G, Martin-Nalda A, Novelli G, Novelli A, Ozcelik T, Palabiyik F, Pan-Hammarström Q, de Diego RP, Planas-Serra L, Pleguezuelo DE, Prando C, Pujol A, Reyes LF, Rivière JG, Rodriguez-Gallego C, Rojas J, Rovere-Querini P, Schlüter 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 SZ, Alosaimi MF, Alsohime FM, Baris-Feldman H, Butte MJ, Constantinescu SN, Cooper MA, Dalgard CL, Fellay J, Heath JR, Lau YL, Lifton RP, Maniatis T, Mogensen TH, von Bernuth H, Le… See abstract for full author list ➔ Matuozzo D, et al. Genome Med. 2024 Jan 6;16(1):6. doi: 10.1186/s13073-023-01278-0. Genome Med. 2024. PMID: 38184654 Free PMC article. No abstract available.

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.

Trial registration: ClinicalTrials.gov NCT04262921 NCT04259892 NCT04352348.

Keywords: COVID-19; Immunity; Rare variants; Type I interferon.

PubMed Disclaimer

Conflict of interest statement

RN and AKK are employees of Invitae and hold equities in the company. RPL is a member of the board of directors of Roche and its subsidiary Genentech. I Meyts holds a chair in Primary Immunodeficiencies and receives research grant from CSL Behring, paid to KUL. JLC reported a patent to PCT/US2021/042741 pending. FT is head of the Centre de Pharmacoépidémiologie (Cephepi) of the Assistance Publique – Hôpitaux de Paris and of the Clinical Research Unit of Pitié-Salpêtrière hospital, both these structures have received unrestricted research funding and grants for the research projects handled and fees for consultant activities from a large number of pharmaceutical companies, that have contributed indiscriminately to the salaries of its employees. FT is not employed by these structures and did not receive any personal remuneration from these companies. The remaining authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Type I IFN immunity genes associated with life-threatening COVID-19. Inborn errors of type I IFN immunity and autoantibodies neutralizing type I IFNs (α, β, ω) underlie life-threatening COVID-19 pneumonia by interfering with type I IFN immunity in respiratory epithelial cells (RECs) and blood plasmacytoid dendritic cells (pDCs). SARS-CoV-2 infection can induce type I IFN production in a TLR3-dependent manner in tissue-resident RECs (which express TLR3 but not TLR7) and in a TLR7-dependent manner in circulating pDCs (which express TLR7 but not TLR3). IRF7 is constitutively expressed in pDCs, at higher levels than in other cell types, whereas it is mostly induced by viral infection in RECs. Reported in red are the 13 genes (IFNAR1, IFNAR2, IRF3, IRF7, IRF9, IKBKG, STAT1, STAT2, TBK1, TICAM1, TLR3, TRAF3, and UNC93B1) investigated in a previous study [15]; TYK2 and TLR7 were subsequently shown to underlie severe COVID-19 [19, 30]
Fig. 2
Fig. 2
Principal component analysis of patients with life-threatening COVID-19 (red) and SARS-CoV-2-infected controls (green). Principal component analysis (PCA) was performed with PLINK v1.9 software [40] on a pruned subset of ~ 14,600 exonic SNPs in linkage equilibrium (maximum r2 value for linkage disequilibrium of 0.4 between pairs of SNPs) with a minor allele frequency (MAF) > 1%, call rate > 99% and P value for departure from Hardy–Weinberg equilibrium > 10.−5. Samples were of diverse ethnic origins, including European (EUR), admixed American (AMR), North African (NAFR), sub-Saharan African (AFR), Middle Eastern (ME), South Asian (SAS), and East Asian (EAS)
Fig. 3
Fig. 3
Manhattan plot for genome-wide burden analysis under the co-dominant (top) and recessive (bottom) models. For each gene, the negative log-transformed p value of the joint analysis for the most significant variant set under a co-dominant (top) or recessive (bottom) model is plotted. For each gene, variant sets providing inconsistent results across the joint analysis, the trans-ethnic meta-analysis, and the trans-pipeline meta-analysis (i.e., P < 0.001 in the joint analysis and P > 0.05 in the trans-ethnic or trans-pipeline meta-analysis) were discarded. The red lines represent the significance threshold after Bonferroni correction to account for the total number of independent tests (P = 4.61 × 10−7 under a co-dominant model and 1.85 × 10−6 under a recessive model). The names of the top-ranked genes with a joint P < 10−4 are shown in red for rare variants associated with an increase in the risk of critical COVID-19 and in blue otherwise
See this image and copyright information in PMC

Update of

  • 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, Manry J, Seeleuthner Y, Zhang Y, Bolze A, Chaldebas M, Milisavljevic B, Zhang P, Gervais A, Bastard P, Asano T, Bizien L, Barzaghi F, Abolhassani H, Tayoun AA, Aiuti A, Darazam IA, Allende LM, Alonso-Arias R, Arias AA, Aytekin G, Bergman P, Bondesan S, Bryceson YT, Bustos IG, Cabrera-Marante O, Carcel S, Carrera P, Casari G, Chaïbi K, Colobran R, Condino-Neto A, Covill LE, El Zein L, Flores C, Gregersen PK, Gut M, Haerynck F, Halwani R, Hancerli S, Hammarström L, Hatipoğlu N, Karbuz A, Keles S, Kyheng C, Leon-Lopez R, Franco JL, Mansouri D, Martinez-Picado J, Akcan OM, Migeotte I, Morange PE, Morelle G, Martin-Nalda A, Novelli G, Novelli A, Ozcelik T, Palabiyik F, Pan-Hammarström Q, Pérez de Diego R, Planas-Serra L, Pleguezuelo DE, Prando C, Pujol A, Reyes LF, Rivière JG, Rodriguez-Gallego C, Rojas J, Rovere-Querini P, Schlüter 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 SZ, Baris-Feldman H, Butte MJ, Constantinescu SN, Cooper MA, Dalgard CL, Fellay J, Heath JR, Lau YL, Lifton RP, Maniatis T, Mogensen TH, von Bernuth H, Lermine A, Vidaud M, Boland A, Del… See abstract for full author list ➔ Matuozzo D, et al. medRxiv [Preprint]. 2022 Oct 25:2022.10.22.22281221. doi: 10.1101/2022.10.22.22281221. medRxiv. 2022. Update in: Genome Med. 2023 Apr 5;15(1):22. doi: 10.1186/s13073-023-01173-8. PMID: 36324795 Free PMC article. Updated. Preprint.

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