Effects of IFIH1 rs1990760 variants on systemic inflammation and outcome in critically ill COVID-19 patients in an observational translational study

  1. Laura Amado-Rodríguez
  2. Estefania Salgado del Riego
  3. Juan Gomez de Ona
  4. Inés López Alonso
  5. Helena Gil-Pena
  6. Cecilia López-Martínez
  7. Paula Martín-Vicente
  8. Antonio Lopez-Vazquez
  9. Adrian Gonzalez Lopez
  10. Elias Cuesta-Llavona
  11. Raquel Rodriguez-Garcia
  12. Jose Antonio Boga
  13. Marta Elena alvarez-Arguelles
  14. Juan Mayordomo-Colunga
  15. Jose Ramon Vidal-Castineira
  16. Irene Crespo
  17. Margarita Fernandez
  18. Loreto Criado
  19. Victoria Salvadores
  20. Francisco Jose Jimeno-Demuth
  21. Lluis Blanch
  22. Belen Prieto
  23. Alejandra Fernandez-Fernandez
  24. Carlos Lopez-Larrea
  25. Eliecer Coto
  26. Guillermo M Albaiceta

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Abstract

Variants in IFIH1 , a gene coding the cytoplasmatic RNA sensor MDA5, regulate the response to viral infections. We hypothesized that IFIH1 rs199076 variants would modulate host response and outcome after severe COVID-19.

Methods:

Patients admitted to an intensive care unit (ICU) with confirmed COVID-19 were prospectively studied and rs1990760 variants determined. Peripheral blood gene expression, cell populations, and immune mediators were measured. Peripheral blood mononuclear cells from healthy volunteers were exposed to an MDA5 agonist and dexamethasone ex-vivo, and changes in gene expression assessed. ICU discharge and hospital death were modeled using rs1990760 variants and dexamethasone as factors in this cohort and in-silico clinical trials.

Results:

About 227 patients were studied. Patients with the IFIH1 rs1990760 TT variant showed a lower expression of inflammation-related pathways, an anti-inflammatory cell profile, and lower concentrations of pro-inflammatory mediators. Cells with TT variant exposed to an MDA5 agonist showed an increase in IL6 expression after dexamethasone treatment. All patients with the TT variant not treated with steroids survived their ICU stay (hazard ratio [HR]: 2.49, 95% confidence interval [CI]: 1.29–4.79). Patients with a TT variant treated with dexamethasone showed an increased hospital mortality (HR: 2.19, 95% CI: 1.01–4.87) and serum IL-6. In-silico clinical trials supported these findings.

Conclusions:

COVID-19 patients with the IFIH1 rs1990760 TT variant show an attenuated inflammatory response and better outcomes. Dexamethasone may reverse this anti-inflammatory phenotype.

Funding:

Centro de Investigación Biomédica en Red (CB17/06/00021), Instituto de Salud Carlos III (PI19/00184 and PI20/01360), and Fundació La Marató de TV3 (413/C/2021).

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  1. Version published to 10.7554/elife.73012 on eLife
  2. ScreenIT

    SciScore for 10.1101/2021.07.03.21259946: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    EthicsIRB: Study design: This single-center prospective, observational study was approved (ref. 2020/188) by the Clinical Research Ethics Committee of Principado de Asturias (Spain).
    Consent: Informed consent was obtained from each participant or next of kin.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    The generated sequences were mapped and counted using Salmon v1.4 software (11).
    Salmon
    suggested: (Salmon, RRID:SCR_017036)
    Raw counts were compared between groups using DESeq2 (12).
    DESeq2
    suggested: (DESeq, RRID:SCR_000154)
    Genes with differential expression (adjusted p-value<0.05, corrected using a false discovery rate of 0.05) were analyzed using Ingenuity Pathway Analysis (Qiagen, USA) to identify overrepresented gene sets and networks.
    Ingenuity Pathway Analysis
    suggested: (Ingenuity Pathway Analysis, RRID:SCR_008653)

    Results from OddPub: Thank you for sharing your code and data.

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    Our work has several limitations. First, the results must be validated in an independent cohort. Our in-silico simulations reinforce the external validity of our findings, but a pharmacogenomic analysis of patients included in clinical trials is warranted for confirmation. Second, steroid treatment was not randomized, so we cannot discard other underlying factors responsible for the observed differences. Although there could be confounding by indication, there were no baseline differences among groups suggesting a higher severity in steroid-treated patients. Moreover, there are significant differences between genotypes irrespective of the treatment received. In addition, in-silico and ex-vivo experiments are congruent with the observed clinical results, supporting the differential effects of steroid therapy in IFIH1 rs1990760 variants. Third, the favourable outcome of patients with a TT allele without steroids is based on a small sample size. As steroids are now the standard of care for severe COVID-19, this sample size cannot be increased outside a hypothetical clinical trial focused of personalized steroid therapy according to IFIH1 rs1990760 variants. However, similar reduced numbers have served to identify other variants in the immune response (34), and the related finding of increased mortality in this genotype after steroid therapy compared to all other variants is supported by a larger sample. In addition, our sample is representative of European population with a limi...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

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  3. Version published to 10.1101/2021.07.03.21259946v1 on medRxiv