IFIH1-mediated post-transcriptional regulation of PTTG1 promotes proliferation and affects PHA-848125 sensitivity and prognosis in oropharyngeal carcinoma.

The pituitary tumor-transforming gene 1 (PTTG1) is an oncogene involved in chromosomal segregation, DNA repair, apoptosis, and metabolism. PTTG1 can be used for clinical diagnosis and treatment and is a potential target for oropharyngeal carcinoma. The proliferation and viability of Cal27 and FaDu cells were assessed using the CCK-8 assay. Real-time PCR and western blotting, respectively, were used to analyze the mRNA and protein expression levels of PTTG1 and IFIH1. The interaction between PTTG1 mRNA and the translational regulatory protein IFIH1 was analyzed using RNA pull-down, RNA immunoprecipitation, and luciferase reporter assays. PTTG1 protein was significantly overexpressed in oropharyngeal carcinoma, whereas PTTG1 mRNA was not. We hypothesized that a translation regulatory protein plays a post-transcriptional role in PTTG1. The IFIH1 protein specifically bound to the 42-52 nt region of PTTG1 mRNA, promoted the translation of PTTG1, and promoted the proliferation of oropharyngeal cancer cells. Administration of the PTTG1 inhibitor PHA-848125 and silencing of IFIH1 synergistically decreased the expression of PTTG1, inhibited the proliferation of oropharyngeal cancer cells, and indicated a good prognosis. We found that the IFIH1-PTTG1 axis could regulate the PHA-848125 response and functionally mediate inter-individual oropharyngeal cancer susceptibility and prognosis. This study aimed to confirm the upstream regulatory genes of PTTG1 and further investigate the specific interactions in this signaling pathway, which will provide a new approach for the treatment of oropharyngeal carcinoma.

Identifying the association between polymorphisms in the GZMB and IFIH1 genes and psoriasis in Egyptians.

OBJECTIVES: This study aims to examine whether the genetic variants in the genes for Granzyme B (GZMB) and Interferon Induced with Helicase C domain 1 (IFIH1) were associated with psoriasis. BACKGROUND: Psoriasis, a papulosquamous skin disease, was initially thought of as a disorder primarily of epidermal keratinocytes but is now recognized as one of the most common immune-mediated disorders. It is caused by the interplay between multiple genetic and environmental risk factors. SUBJECTS AND METHODS: This case-control study has 65 participants with psoriasis and 65 healthy controls. Real-time PCR was used to genotype GZMB (rs8192917) and IFIH1 (rs35667974). RESULTS: Genotype occurrence and allelic spreading for both SNPs are in Hardy - Weinberg equilibrium. The genotype and allele distributions of rs35667974 showed no differences between the studied groups. Regarding rs8192917, compared to Group II, there is a statistically significant rise in the CC genotype and C allele in Group I. Higher PASI scores are detected in the C/C and C/T genotypes more than the T/T genotype. Univariate and multivariate analyses revealed that BMI, catalase, MDA, and rs8192917 (C/C) are associated with psoriasis. CONCLUSION: GZMB rs8192917 was significantly related to psoriasis risk; its C allele is likewise associated with psoriasis vulnerability. However, our investigation found no link between rs35667974 and psoriasis.

The IFIH1-A946T risk variant promotes diabetes in a sex-dependent manner.

Type 1 diabetes (T1D) is an autoimmune disease in which pancreatic islet ß-cells are attacked by the immune system, resulting in insulin deficiency and hyperglycemia. One of the top non-synonymous single-nucleotide polymorphisms (SNP) associated with T1D is in the interferon-induced helicase C domain-containing protein 1 (IFIH1), which encodes an anti-viral cytosolic RNA sensor. This SNP results in an alanine to threonine substitution at amino acid 946 (IFIH1A946T) and confers an increased risk for several autoimmune diseases, including T1D. We hypothesized that the IFIH1A946T risk variant, (IFIH1R) would promote T1D pathogenesis by stimulating type I interferon (IFN I) signaling leading to immune cell alterations. To test this, we developed Ifih1R knock-in mice on the non-obese diabetic (NOD) mouse background, a spontaneous T1D model. Our results revealed a modest increase in diabetes incidence and insulitis in Ifih1R compared to non-risk Ifih1 (Ifih1NR) mice and a significant acceleration of diabetes onset in Ifih1R females. Ifih1R mice exhibited a significantly enhanced interferon stimulated gene (ISG) signature compared to Ifih1NR, indicative of increased IFN I signaling. Ifih1R mice exhibited an increased frequency of plasma cells as well as tissue-dependent changes in the frequency and activation of CD8+ T cells. Our results indicate that IFIH1R may contribute to T1D pathogenesis by altering the frequency and activation of immune cells. These findings advance our knowledge on the connection between the rs1990760 variant and T1D. Further, these data are the first to demonstrate effects of Ifih1R in NOD mice, which will be important to consider for the development of therapeutics for T1D.

Influence of the HLA-Cw6 Allele and IFIH1/MDA5 Gene Variants on the Cardiometabolic Risk Profile of Patients with Psoriatic Disease.

BACKGROUND: Cardiovascular comorbidity is a common companion of psoriasis and psoriatic arthritis (PsA). Recently, a significant link has been found between the HLA-Cw6 allele and a better cardiometabolic profile in these patients. We aimed to check this finding in our setting. METHODS: A cross-sectional observational study (n: 572 psoriasis patients, 30% with PsA) was conducted. Different study variables were collected in detail, as well as classic cardiometabolic risk factors. The distribution of the HLA-Cw6 allele and the IFIH1/MDA5 gene variants previously linked to disease risk were determined in the study cohort and stratified according to the cardiometabolic comorbidity. Linear and logistic regression models were constructed to analyze these associations. RESULTS: The study cohort included 309 men and 263 women, with a mean age of 46.7 years (SD 14.5) and a mean disease duration of 19.4 years (SD 14.8). We confirmed the known association between HLA-Cw6 and type I psoriasis (familial, severe, and early onset). Psoriasis severity (OR: 2.14), female sex (OR: 1.63), and the IFIH1/MDA5 rs1990760 TT genotype (OR: 1.62) were significantly related to PsA, while HLA-Cw6 was protective (OR: 0.65). HLA-Cw6 carriers showed a lower waist perimeter, lower BMI, and lower risk of both hypertension (OR: 0.52, p < 0.001) and diabetes (OR: 0.36, p < 0.001), but these findings were no longer apparent upon adjusting the regression models. No IFIH1/MDA5 gene variant was associated with any cardiometabolic risk factor. CONCLUSIONS: The influence of HLA-Cw6 on the cardiometabolic risk profile of psoriatic patients seems to be explained by other factors (age, sex, duration of the disease or arthritis) and not by this biomarker itself.

A study on the IFIH1 gene polymorphism in children with type 1 diabetes in Tianjin area / 中华内分泌代谢杂志

The blood samples of 102 type 1 diabetic children aged under 15 years and 127 normal children were collected and their genomic DNAs were extracted. The single nucleotide polymorphisms rs1990760 and rs35744605 of interferon induced with helicase C domain 1(IFIH1)gene were detected. The results showed that the allele of IFIH1 rs35744605 in diabetes group and control group was the wild type G allele. The frequency of IFIH1 rs1990760 A allele in diabetes group was higher than that in control group(22. 1％ vs 13. 0％ ,P=0. 015), suggesting that IFIH1 rs1990760 A allele is associated with type 1 diabetes in Tianjin area.

The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus / O papel do interferon induzido com o domínio C da helicase 1 (IFIH1) no desenvolvimento do diabetes melito tipo 1

Type 1 diabetes mellitus (T1DM) is a chronic, progressive, autoimmune disease characterized by metabolic decompensation frequently leading to dehydration and ketoacidosis. Viral pathogens seem to play a major role in triggering the autoimmune destruction that leads to the development of T1DM. Among several viral strains investigated so far, enteroviruses have been consistently associated with T1DM in humans. One of the mediators of viral damage is the double-stranded RNA (dsRNA) generated during replication and transcription of viral RNA and DNA. The IFIH1 gene encodes a cytoplasmic receptor of the pattern-recognition receptors (PRRs) family that recognizes dsRNA, playing a role in the innate immune response triggered by viral infection. Binding of dsRNA to this PRR triggers the release of proinflammatory cytokines, such as interferons (IFNs), which exhibit potent antiviral activity, protecting uninfected cells and inducing apoptosis of infected cells. The IFIH1 gene appears to play a major role in the development of some autoimmune diseases, and it is, therefore, a candidate gene for T1DM. Within this context, the objective of the present review was to address the role of IFIH1 in the development of T1DM.

O diabetes melito tipo 1 (T1DM) é uma doença autoimune crônica e progressiva caracterizada por descompensações metabólicas frequentemente acompanhadas por desidratação e cetoacidose. Os agentes virais parecem ter um papel importante no desencadeamento da destruição autoimune que leva ao desenvolvimento do T1DM. Entre as cepas virais estudadas até agora, a família dos enterovírus foi consistentemente associada ao surgimento da doença em humanos. Um dos mediadores do dano viral é o RNA fita dupla (RNAfd) gerado durante a replicação e transcrição de RNA e DNA viral. O gene IFIH1 codifica um receptor citoplasmático pertencente à família dos pattern-recognition receptors (PRRs) que reconhece o RNAfd, tendo um papel importante na resposta imune inata desencadeada por infecção viral. A ligação do RNAfd a essa PRR desencadeia a liberação de citocinas pró-inflamatórias como interferons (IFNs), os quais exibem uma potente ação antiviral e têm como objetivo proteger as células não infectadas e induzir apoptose naquelas já contaminadas. O gene IFIH1 parece ter uma participação importante no desenvolvimento de algumas doenças autoimunes. Por isso, esse gene é um candidato ao desenvolvimento do T1DM. Dentro desse contexto, o objetivo da presente revisão foi abordar o papel do IFIH1 no desenvolvimento do T1DM.

Genética de la diabetes mellitus tipo 1 / Genetic of type 1 diabetes mellitus

Type 1 diabetes (T1D) results from autoimmune-mediated destruction of the pancreatic beta cells, a process that is conditioned by multiple genes and environmental factors. The process that destroys the pancreatic b cells in T1D is mediated by T cells and leads to a complex phenotype influenced by multiple factors. It has been more than 30 years since the publication of the first evidence suggesting the involvement of a specific chromosomal region, HLA, in modulating the risk for T1D. HLA locus has been known for decades to contribute strongly with the attributable to genetic risk. In addition to HLA, many proposed candidate loci have been described that are associated with risk of developing the disease, including the insulin gene (INS), PTPN22,CTLA-4, PD-1, IL2-RA and IFIH1 which together do not contribute more than 15 percent of the risk. This review compiled the data on T1D genes and discusses the major genetic impact of these genetic aspects in T1D etiology.