Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19

Povysil, Gundula; Butler‐Laporte, Guillaume; Shang, Ning; Wang, Chen; Khan, Atlas; Alaamery, Manal; Nakanishi, Teruyuki; Zhou, Sirui; Forgetta, Vincenzo; Eveleigh, Robert; Bourgey, Mathieu; Aziz, Naveed; Jones, Steven J.M.; Knoppers, Bartha Maria; Scherer, Stephen W.; Strug, Lisa J.; Lepage, Pierre; Ragoussis, Jiannis; Bourque, Guillaume; Alghamdi, Jahad; Aljawini, Nora; Albes, Nour; Al-Afghani, Hani M.; Alghamdi, Bader; Almutairi, Mansour S; Mahmoud, Ebrahim; Abu-Safieh, Leen; Bardisy, Hadeel El; Harthi, Fawz S. Al; Alshareef, Abdulraheem; Suliman, Bandar Ali; Alqahtani, Saleh A.; Almalik, Abdulaziz; Alrashed, May; Massadeh, Salam; Mooser, Vincent; Lathrop, Mark; Mohamed, Fawzy; Arabi, Yaseen M.; Mbarek, Hamdi; Saad, Chadi; Al‐Muftah, Wadha; Jung, Junghyun; Mangul, Serghei; Badji, Radja; Thani, Asma Al; Ismail, Said I.; Gharavi, Ali G.; Abedalthagafi, Malak; Richards, J. Brent; Goldstein, David; Kiryluk, Krzysztof

doi:10.1172/jci147834

Cited by 54 publications

(54 citation statements)

References 7 publications

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“…Further, these results were unchanged when testing severe cases of COVID-19 (n ¼ 1,304) or when restricting the burden tests to include variants with an MAF < 1% or singleton variants (Table S7). Therefore, in alignment with a similar report, 23 we also found no evidence for an association between RVs in these 13 interferon-signaling genes.…”

supporting

confidence: 89%

“…16 Second, we highlight an association between higher risk of COVID-19 and an ultra-rare missense variant in ZC3HAV1 (rs769102632:A, MAF ¼ 0.002%; p ¼ 3EÀ8; OR ¼ 26.7; 95% CI 8.37-85.38; Figure S1), a gene that encodes a zinc finger antiviral protein 19,20 that inhibits SARS-CoV-2 replication, 21 potentially by upregulating type I interferon responses. 22 Given the potential significance of this finding, we attempted to replicate the ZC3HAV1 rs769102632:A association in an additional 6,223 individuals with COVID-19 with exome or whole-genome sequence data generated as part of the GenOMICC (n ¼ 4,851), 11 Columbia University COVID-19 Biobank (n ¼ 1,152), and Biobanque Quebec (n ¼ 220) 23 studies. We found no carriers for this variant in these additional COVID-19 cases (Table S5) when we expected about four given the observed allele frequency in cases in our study (three and one carriers expected in individuals of African and European ancestry, respectively).…”

mentioning

confidence: 99%

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Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

Kosmicki

Horowitz

Banerjee

et al. 2021

The American Journal of Human Genetics

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Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes coronavirus disease-19 (COVID-19), a respiratory illness that can result in hospitalization or death. We used exome-sequence data to investigate associations between rare genetic variants and seven COVID-19 outcomes in 586,157 individuals, including 20,952 with COVID-19. After accounting for multiple testing, we did not identify any clear associations with rare variants either exome-wide or when specifically focusing on (i) 13 interferon pathway genes in which rare deleterious variants have been reported in individuals with severe COVID-19; (ii) 281 genes located in susceptibility loci identified by the COVID-19 Host Genetics Initiative; or (iii) 32 additional genes of immunologic relevance and/or therapeutic potential. Our analyses indicate there are no significant associations with rare protein-coding variants with detectable effect sizes at our current sample sizes. Analyses will be updated as additional data become available, with results publicly available through the Regeneron Genetics Center COVID-19 Results Browser.

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supporting

confidence: 89%

mentioning

confidence: 99%

Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

Kosmicki

Horowitz

Banerjee

et al. 2021

The American Journal of Human Genetics

Self Cite

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“…For example, some toll-like receptors (TLRs) are circadian regulated, with TLR9 having non-canonical E-box motifs (Silver et al, 2012). The interplay between IFNs and COVID-19 disease progression is complex, and despite initial findings, there is currently no clear evidence for a genetic immune predisposition to severe COVID-19 (Meisel et al, 2021;Povysil et al, 2021). Nevertheless, there is evidence at early iScience Article stages of infection that SARS-CoV-2 is sensitive to ISG induction and IFNs are being discussed as a treatment option (Cheemarla et al, 2021;Hasselbalch et al, 2021;Yang et al, 2021).…”

Section: Discussionmentioning

confidence: 99%

The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells

Zhuang¹,

Tsukuda²,

Wrensch³

et al. 2021

iScience

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The COVID-19 pandemic, caused by SARS-CoV-2 coronavirus, is a global health issue with unprecedented challenges for public health. SARS-CoV-2 primarily infects cells of the respiratory tract via Spike glycoprotein binding to angiotensin-converting enzyme (ACE2). Circadian rhythms coordinate an organism’s response to its environment and can regulate host susceptibility to virus infection. We demonstrate that silencing the circadian regulator Bmal1 or treating lung epithelial cells with the REV-ERB agonist SR9009 reduce ACE2 expression and inhibit SARS-CoV-2 entry and replication. Importantly, treating infected cells with SR9009 limits SARS-CoV-2 replication and secretion of infectious particles, showing that post-entry steps in the viral life cycle are influenced by the circadian system. Transcriptome analysis revealed that Bmal1 silencing induced interferon stimulated gene transcripts in Calu-3 lung epithelial cells, providing a mechanism for the circadian pathway to limit SARS-CoV-2 infection. Our study highlights alternative approaches to understand and improve therapeutic targeting of SARS-CoV-2.

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“…This observation was confirmed in independent patient cohorts ( 94 – 96 ). In addition, inborn errors of type-I IFN immunity were reported in some -but not all- examined cohorts of patients with life-threatening COVID-19 ( 97 – 99 ). Given these observations, and the life-threatening pneumonia requiring mechanical ventilation in the first three reported APECED patients with COVID-19 ( 92 , 100 ), we performed a follow-up international observational study of 22 SARS-CoV-2–infected APECED patients ( 84 ).…”

Section: Pathogenesis Of Aire Deficiencymentioning

confidence: 99%

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

2021

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Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), also known as autoimmune polyglandular syndrome type-1 (APS-1), is a rare monogenic autoimmune disease caused by loss-of-function mutations in the autoimmune regulator (AIRE) gene. AIRE deficiency impairs immune tolerance in the thymus and results in the peripheral escape of self-reactive T lymphocytes and the generation of several cytokine- and tissue antigen-targeted autoantibodies. APECED features a classic triad of characteristic clinical manifestations consisting of chronic mucocutaneous candidiasis (CMC), hypoparathyroidism, and primary adrenal insufficiency (Addison's disease). In addition, APECED patients develop several non-endocrine autoimmune manifestations with variable frequencies, whose recognition by pediatricians should facilitate an earlier diagnosis and allow for the prompt implementation of targeted screening, preventive, and therapeutic strategies. This review summarizes our current understanding of the genetic, immunological, clinical, diagnostic, and treatment features of APECED.

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Rare loss-of-function variants in type I IFN immunity genes are not associated with severe COVID-19

Cited by 54 publications

References 7 publications

Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

Pan-ancestry exome-wide association analyses of COVID-19 outcomes in 586,157 individuals

The circadian clock component BMAL1 regulates SARS-CoV-2 entry and replication in lung epithelial cells

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy

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