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.

Interferon induced with helicase C domain 1 (IFIH1) single-nucleotide polymorphisms (SNP) rs1990760, rs3747517, and rs10930046 have been shown to be closely related to the risk of autoimmune diseases. The aim of this study was firstly to examine the association of the rs1990760 with type 1 diabetes (T1D) in a Chinese population. Secondly, to assess the association of SNP rs1990760, rs3747517, and rs10930046 with autoimmune diseases susceptibility.
A total of 1,273 T1D patients and 1,010 healthy control subjects in a Chinese population were enrolled in this case-control study. Subsequently, we performed a meta-analysis on the association of the SNP rs1990760, rs3747517, and rs10930046 in the IFIH1 gene with susceptibility to autoimmune diseases. The random and fixed genetic effects models were used to evaluate the association and the effect sizes, including odds ratios (OR) and 95% confidence intervals (CI). Stratification analyses based on ethnicity and the type of autoimmune diseases were performed.
IFIH1 SNP rs1990760 was not associated with a significant risk of T1D in the Chinese population in the case-control study. A total of 35 studies including 70,966 patients and 124,509 controls were identified and included in the meta-analysis. The results displayed significant associations between IFIH1 rs1990760 A allele and rs3747517 C allele and autoimmune diseases risk (OR=1.09, 95% CI: 1.01~1.17; OR=1.24, 95% CI: 1.15~1.25, respectively). Stratified analysis indicated a significant association rs1990760 and rs3747517 with autoimmune diseases risk in the Caucasian population (OR=1.11, 95% CI: 1.02~1.20, OR=1.29, 95% CI: 1.18~1.41, respectively).
This study revealed no association between IFIH1 SNP rs1990760 and T1D in Chinese. Furthermore, the meta-analysis indicated that rs1990760 and rs3747517 polymorphisms, confer susceptibility to autoimmune diseases, especially in the Caucasian population.

Hepatitis C remains a major public health problem in the world. The host immune system plays a key role in viral clearance. This study aimed to investigate the connection between retinoic acid-inducible gene I-like (RIG-I-like) receptor gene polymorphism and hepatitis C chronicity in the Chinese Han population. The current study genotyped three SNPs (IFIH1 rs10930046 and DHX58 rs2074158, rs2074160) to assess their association with the chronicity of hepatitis C virus (HCV) infection among 1,590 participants (590 spontaneous HCV clearance cases and 1,000 persistent infection patients). Our research shows that DHX58 rs2074158-G allele (dominant model: adjusted OR = 1.53, 95% CI [1.20-1.95], P = 0.001; additive model: adjusted OR = 1.50, 95% CI [1.27-1.78], P < 0.001) and IFIH1 rs10930046-C allele (additive model: adjusted OR = 1.26, 95% CI [1.07-1.49], P = 0.005) were associated with chronic hepatitis C (CHC). And the risk of CHC increased in people carrying more unfavorable genotypes (rs2074158-AG/GG or rs10930046-CC), with the chronic rates for genotypes number from zero to two in 60.69%, 57.33%, and 85.93%, respectively (adjusted OR = 3.64, 95% CI [2.18-6.08]; P < 0.001). Genetic polymorphism of IFIH1 and DHX58 may be related to CHC in the Chinese Han population. Furthermore, the risk of CHC increases as the number of unfavorable genotypes carried by the HCV-infected person increases. IFIH1 rs10930046, DHX58 rs2074158, age, ALT, and AST levels were all independent predictors of CHC.

BACKGROUND: A growing body of research has shown that the phenotypic change in macrophages from M0 to M1 is essential for the start of the inflammatory process in septic acute respiratory distress syndrome (ARDS). Potential treatment targets might be identified with more knowledge of the molecular regulation of M1 macrophages in septic ARDS.
METHODS: A multi-microarray interrelated analysis of high-throughput experiments from ARDS patients and macrophage polarization was conducted to identify the hub genes associated with macrophage M1 polarization and septic ARDS. Lipopolysaccharide (LPS) and Poly (I:C) were utilized to stimulate bone marrow-derived macrophages (BMDMs) for M1-polarized macrophage model construction. Knock down of the hub genes on BMDMs via shRNAs was used to screen the genes regulating macrophage M1 polarization in vitro. The cecal ligation and puncture (CLP) mouse model was constructed in knockout (KO) mice and wild-type (WT) mice to explore whether the screened genes regulate macrophage M1 polarization in septic ARDS in vivo. ChIP-seq and further experiments on BMDMs were performed to investigate the molecular mechanism.
RESULTS: The bioinformatics analysis of gene expression profiles from a clinical cohort of 26 ARDS patients and macrophage polarization found that the 5 hub genes (IFIH1, IRF1, STAT1, IFIT3, GBP1) may have a synergistic effect on macrophage M1 polarization in septic ARDS. Further in vivo investigations indicated that IFIH1, STAT1 and IRF1 contribute to macrophage M1 polarization. The histological evaluation and immunohistochemistry of the lungs from the IRF1-/- and WT mice indicated that knockout of IRF1 markedly alleviated CLP-induced lung injury and M1-polarized infiltration. Moreover, the molecular mechanism investigations indicated that knockdown of IFIH1 markedly promoted IRF1 translocation into the nucleus. Knockout of IRF1 significantly decreases the expression of STAT1. ChIP-seq and PCR further confirmed that IRF1, as a transcription factor of STAT1, binds to the promoter region of STAT1.
CONCLUSIONS: IRF1 was identified as the key molecule that regulates macrophage M1polarization and septic ARDS development in vivo and in vitro. Moreover, as the adaptor in response to infection mimics irritants, IFIH1 promotes IRF1 (transcription factor) translocation into the nucleus to initiate STAT1 transcription.

Background: Psoriasis is a common immune-mediated hyperproliferative skin dysfunction with known genetic predisposition. Gene-gene interaction (e.g., between HLA-C and ERAP1) in the psoriasis context has been reported in various populations. As ERAP1 has been recognized as a psoriasis susceptibility gene and plays a critical role in antigen presentation, we performed this study to identify interactions between ERAP1 and other psoriasis susceptibility gene variants. Methods: We validated psoriasis susceptibility gene variants in an independent cohort of 5,414 patients with psoriasis and 5,556 controls. Multifactor dimensionality reduction (MDR) analysis was performed to identify the interaction between variants significantly associated with psoriasis in the validation cohort and ERAP1 variants. We then conducted a meta-analysis of those variants with datasets from exome sequencing, target sequencing, and validation analyses and used MDR to identify the best gene-gene interaction model, including variants that were significant in the meta-analysis and ERAP1 variants. Results: We found that 19 of the replicated variants were identified with p < 0.05 and detected six single-nucleotide polymorphisms of psoriasis susceptibility genes in the meta-analysis. MDR analysis revealed that the best predictive model was that between the rs27044 polymorphism of ERAP1 and the rs7590692 polymorphism of IFIH1 (cross-validation consistency = 9/10, test accuracy = 0.53, odds ratio = 1.32 (95% CI, 1.09-1.59), p < 0.01). Conclusion: Our findings suggest that the interaction between ERAP1 and IFIH1 affects the development of psoriasis. This hypothesis needs to be tested in basic biological studies.

UNASSIGNED: The aim of the present study was to investigate the association of single-nucleotide polymorphisms (SNPs) in the macrophage migration inhibiting factor (MIF), interferon-induced Helicase C domain 1 (IFIH1), interleukin-6 (IL6) genes, circulating levels with non-segmental vitiligo (NSV) susceptibility in the Chinese population, and to analyze the relationships between gene polymorphisms and clinical characteristics of vitiligo.
UNASSIGNED: In this study, genotyping was conducted in 155 patients with NSV and 117 unaffected controls using polymerase chain reaction and snapshot technique. Serum concentrations were determined by ELISA kit.
UNASSIGNED: There were strong associations between IFIH1 H843R and IL6-572G/C polymorphisms and NSV susceptibility (p = 0.013; p = 0.009). In contrast to previous studies, we found no significant difference in the MIF-173G/C polymorphism between the two groups. In addition, the frequency of allelic distribution for MIF-173G/C in patients with active NSV was significantly higher than stable NSV (p = 0.011), and IFIH1 H843R with early-onset (≤ 20), active or family history of NSV was significantly higher than late-onset (> 20), stable or no family history of NSV (p = 0.033; p = 0.045; p = 0.039). Serum concentrations of MIF were higher in patients with active NSV, serum IFIH1 and IL6 concentrations were related to the presence of polymorphisms in patients with NSV (p = 0.009; p = 0.011).
UNASSIGNED: Our results suggested that IFIH1 H843R and IL6-572G/C gene polymorphisms and expression levels are obviously correlated with the onset of NSV. MIF-173G/C allele and serum concentrations may be associated with active NSV, and IFIH1 H843R allele may be associated with youth, active or family history of NSV.

Interferon-induced with helicase C domain 1 (IFIH1) is a cytosolic sensor of dsRNA that induces an anti-viral Type I interferon (IFN) state. A gain-of-function mutation in IFIH1 can cause increased Type I IFN activity and is clinically associated with Aicardi-Goutières syndrome (AGS). AGS is a multisystem disease, characterized as an early-onset progressive encephalopathy with basal ganglia calcification and systemic lupus erythematosus-like features. Gastrointestinal manifestation is rare in AGS patients. We described a 10-year-old female patient with a heterozygous IFIH1 gene mutation who presented with gastrointestinal colitis, cystitis and very severe diarrhea as initial major manifestations of AGS. Proteinuria with high titer of antinuclear antibody and anti-double-stranded DNA was found in this patient. She also had growth retardation and a history of seizures (about two episodes each year) but without attacks until 7 years old. Serum cytokines detected by flow cytometry indicated extremely high level of interleukin 6 (1970.1 pg/ml) and IFN-α (204.1 pg/ml). A contrast-enhanced CT scan of the whole abdomen and an intestinal hydro-MRI indicated that the walls of her stomach, small bowel, colon, and bladder were in various degrees of edema and thickened states. Whole exome sequencing analysis indicated that she harbors an IFIH1 heterozygous mutation (c.2336G > A (p.R779H)) in both blood and intestinal samples. Abundant inflammatory cells infiltration into the intestinal epithelium was observed by immunohistochemical staining. Positive staining of caspase 4 and caspase 5 suggested that the signaling pathway of pyroptosis was involved in the mechanism of intestinal inflammation in AGS. Diarrhea was significantly improved after steroids and intravenous immunoglobulin treatments. Gastrointestinal colitis and cystitis can be rare manifestations of AGS with IFIH1 mutation. Caspase and its related inflammasome pathway may involve in the pathogenesis of AGS.

The IFIH1 gene encodes melanoma differentiation-associated gene 5 (MDA5) and has been associated with Aicardi-Goutières syndrome (AGS), Singleton-Merten syndrome (SMS), and other autoimmune diseases. The mechanisms responsible for how a functional change in a single gene can cause so many different phenotypes remain unknown. Moreover, there is significant controversy as to whether these distinct phenotypes represent the same disease continuum or mutation-specific disorders. Here, we describe the case of a patient with a novel c.1465G > T (p.Ala489Ser) mutation in the IFIH1 gene. The patient presented with spastic paraplegia, dystonia, psychomotor retardation, joint deformities, intracranial calcification, abnormal dentition, characteristic facial features, lymphadenopathy, and autoimmunity. His phenotype appeared to represent an overlap of the phenotypes for AGS and SMS. The patient also experienced unexplained pancytopenia, suggesting that the hemic system may have been affected by a gain-of-function mutation in the IFIH1 gene. In summary, we provide further evidence that SMS and AGS exhibit the same disease spectrum following a gain-of-function mutation in the IFIH1 gene. Our data highlight the genetic heterogeneity of these conditions and expand our knowledge of differential phenotypes created by IFIH1 gain-of-function mutation.

Accumulated evidence has demonstrated that the macrophage phenotypic switch from M0 to M1 is crucial in the initiation of the inflammatory process of acute respiratory distress syndrome (ARDS). Better insight into the molecular control of M1 macrophages in ARDS may identify potential therapeutic targets. In the current study, 36 candidate genes associated with the severity of ARDS and simultaneously involved in M1-polarized macrophages were first screened through a weighted network algorithm on all gene expression profiles from the 26 ARDS patients and empirical Bayes analysis on the gene expression profiles of macrophages. STAT1, IFIH1, GBP1, IFIT3, and IRF1 were subsequently identified as hub genes according to connectivity degree analysis and multiple external validations. Among these candidate genes, IFIH1 had the strongest connection with ARDS through the RobustRankAggreg algorithm. It was selected as a crucial gene for further investigation. For in vitro validation, the RAW264.7 cell line and BMDMs were transfected with shIFIH1 lentivirus and plasmid expression vectors of IFIH1. Cellular experimental studies further confirmed that IFIH1 was a novel regulator for promoting M1 macrophage polarization. Moreover, gene set enrichment analysis (GSEA) and in vitro validations indicated that IFIH1 regulated M1 polarization by activating IRF3. In addition, previous studies demonstrated that activation of IFIH1-IRF3 was stimulated by viral RNAs or RNA mimics. Surprisingly, the current study found that LPS could also induce IFIH1-IRF3 activation via a MyD88-dependent mechanism. We also found that only IFIH1 expression without LPS or RNA mimic stimulation could not affect IRF3 activation and M1 macrophage polarization. These findings were validated on two types of macrophages, RAW264.7 cells and BMDMs, which expanded the knowledge on the inflammatory roles of IFIH1 and IRF3, suggesting IFIH1 as a potential target for ARDS treatment.

Forty-nine susceptible loci have been reported to be significantly associated with vitiligo by genome-wide association studies (GWASs) in European-derived whites. To date, some of these reported susceptibility loci have not yet been validated in the Chinese Han population. The purpose of this study was to examine whether the 16 reported susceptible loci in European-derived whites were associated with vitiligo in the Chinese Han population. Imputation was performed using our previous GWAS dataset by IMPUTE v2.2.2. The 16 imputed top single-nucleotide polymorphisms (SNPs) with suggestive signals, together with the reported SNPs, were genotyped in a total of 2581 patients and 2579 controls by the Sequenom MassARRAY system. PLINK 2.0 software was used to perform association analysis. The dbSNP database, HaploReg, and eQTL data were adopted to annotate the biological function of the SNPs. Finally, four SNPs from three loci were significantly associated with vitiligo, including rs3747517 (P = 1.29 × 10-3, OR = 0.87) in 2q24.2, rs4807000 (P = 7.78 × 10-24, OR = 0.66) and rs6510827 (P = 3.65 × 10-5, OR = 1.19) in 19p13.3, and rs4822024 (P = 6.37 × 10-10, OR = 0.67) in 22q13.2. According to the dbSNP database, rs3747517 is a missense variant of IFIH1, rs4807000 and rs6510827 are located in TICAM1, and rs4822024 is located 6 kb upstream of TEF. Further bioinformatics analysis by HaploReg and eQTL found that rs4807000, rs6510827, and rs4822024 are involved in regulating gene expression. Our study revealed the strong association of 2q24.2 (rs3747517), 19p13.3 (rs4807000, rs6510827), and 22q13.2 (rs4822024) with the risk of vitiligo in the Chinese Han population, which implicates common factors for vitiligo across different ethnicities, and helps expand the understanding of the genetic basis of this disease.