The interferon-induced helicase C domain-containing protein 1 gene variant (rs1990760) as an autoimmune-based pathology susceptibility factor

Wawrusiewicz‐Kurylonek, Natalia; Gościk, Joanna; Chorąży, Monika; Siewko, Katarzyna; Posmyk, Renata; Zajkowska, Agata; Citko, Anna; Maciulewski, Rafal; Szelachowska, Małgorzata; Myśliwiec, Janusz; Jastrzębska, Izabella; Kułakowska, Alina; Kochanowicz, Jan; Krętowski, Adam

doi:10.1016/j.imbio.2019.10.013

Cited by 12 publications

(6 citation statements)

References 40 publications

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“…The genotyping strategy was validated by Sanger sequencing of selected individuals from the three genotypes. Based on previous data showing that patients with a TT genotype have a different immune response compared to CC and CT ( Wawrusiewicz-Kurylonek et al, 2020 ; Zhang et al, 2018 ), patients with these two variants were grouped and compared against the TT group.…”

Section: Methodsmentioning

confidence: 99%

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

Amado-Rodríguez

Salgado²,

Oña

et al. 2022

eLife

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Background: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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Section: Methodsmentioning

confidence: 99%

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

Amado-Rodríguez

Salgado²,

Oña

et al. 2022

eLife

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“…However, a study by Wawrusiewicz‐Kurylonek et al. revealed that the polymorphisms within the MDA5 gene had a significant association with susceptibility to MS [18]. Thus, it may be hypothesized that the downregulation of MDA5 in our patients in comparison to healthy controls might be related to their differences regarding the genetic variations.…”

Section: Discussionmentioning

confidence: 83%

The effect of IFN‐β 1a on expression of MDA5 and RIG‐1 in multiple sclerosis patients

Asadikaram

Meimand

Noroozi

et al. 2020

Biotech and App Biochem

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The aims of this study were to compare mRNA levels of melanoma differentiation‐associated protein 5 (MDA5) and retinoic acid‐inducible gene 1 (RIG‐1) in multiple sclerosis (MS) patients in comparison to the healthy controls as well as investigating the effects of IFN‐β 1a on the expression of these molecules. In this study, mRNA levels of MDA5 and RIG‐1 in peripheral leukocytes of 30 new cases of MS patients and 35 healthy controls were evaluated using the real‐time‐PCR method. mRNA levels of MDA5 and RIG‐1 were determined in the MS patients 6 months after treatment with standard doses of IFN‐β 1a. mRNA levels of MDA5 and RIG‐1 were significantly decreased in the MS patients in comparison to the healthy controls. The analysis also revealed that IFN‐β 1a therapy leads to the upregulation of RIG‐1, but not MDA5, in the total MS patients and the female group. MS patients suffer from insufficient expression of MDA5 and RIG‐1, and IFN‐β 1a therapy results in the upregulation of RIG‐1 in the patients, especially in the female patients. Thus, it seems that IFN‐β 1a not only decreased pathogenic inflammatory responses but also modulated the expression of RIG‐1 to protect the patients from infectious diseases and upregulation of IFN‐I in a positive feedback.

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“…First, through the kinase system of the IKK, it activates the transcription factor NF-kB, which causes cell activation and the synthesis of a number of pro-inflammatory cytokines. The second, through the adapter of the TRAF3 protein and the protein kinase TBK1, activates two transcription factors, IRF3 and IRF7, inducing the synthesis of interferons beta and alpha, respectively [63]. Mutations in this gene are significantly associated with various autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and latent autoimmune diabetes LADA) and type 1 diabetes mellitus [64].…”

Section: Ifih1mentioning

confidence: 99%

The Role of Genetic Factors in the Development of Acute Respiratory Viral Infection COVID-19: Predicting Severe Course and Outcomes

et al. 2022

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The aim of this study was to identify single nucleotide variants in genes associated with susceptibility to or severe outcomes of COVID-19. A total of 319 genomic DNA samples from patients with varying degrees of disease severity and 78 control DNA samples from people who had regular or prolonged contact with patients with COVID-19 but did not have clinical manifestations and/or antibodies to SARS-CoV-2. Seven SNPs were identified that were statistically associated with disease risk or severe course, rs1799864 in the CCR2 gene (OR = 2.21), rs1990760 in the IFIH1 gene (OR = 2.41), rs1800629 in the TNF gene (OR = 1.98), rs75603675 in the TMPRSS2 gene (OR = 1.86), rs7842 in the C3AR1 gene (OR = 2.08), rs179008 in the gene TLR7 (OR = 1.85), rs324011 in the C3AR1 gene (OR = 2.08), rs179008 in the TLR7 gene (OR = 1.85), and rs324011 in the STAT6 gene (OR = 1.84), as well as two variants associated with protection from COVID-19, rs744166 in the STAT3 gene (OR = 0.36) and rs1898830 in the TLR2 gene (OR = 0.47). The genotype in the region of these markers can be the criterion of the therapeutic approach for patients with COVID-19.

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The interferon-induced helicase C domain-containing protein 1 gene variant (rs1990760) as an autoimmune-based pathology susceptibility factor

Cited by 12 publications

References 40 publications

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

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

The effect of IFN‐β 1a on expression of MDA5 and RIG‐1 in multiple sclerosis patients

The Role of Genetic Factors in the Development of Acute Respiratory Viral Infection COVID-19: Predicting Severe Course and Outcomes

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