Four Promoters of IRF5 Respond Distinctly to Stimuli and are Affected by Autoimmune-Risk Polymorphisms.
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ABSTRACT:
SUBMITTER: Clark DN
PROVIDER: S-EPMC3819785 | biostudies-literature | 2013
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Interferon regulatory factor (IRF)-5 is a transcription factor involved in type I interferon signaling whose germ line variants have been associated with autoimmune pathogenesis. Since relationships have been observed between development of autoimmunity and responsiveness of melanoma to several types of immunotherapy, we tested whether polymorphisms of IRF5 are associated with responsiveness of melanoma to adoptive therapy with tumor infiltrating lymphocytes (TILs). METHODS:140 TILs were genotyped for four single nucleotide polymorphisms (rs10954213, rs11770589, rs6953165, rs2004640) and one insertion-deletion in the IRF5 gene by sequencing. Gene-expression profile of the TILs, 112 parental melanoma metastases (MM) and 9 cell lines derived from some metastases were assessed by Affymetrix Human Gene ST 1.0 array. RESULTS:Lack of A allele in rs10954213 (G > A) was associated with non-response (p < 0.005). Other polymorphisms in strong linkage disequilibrium with rs10954213 demonstrated similar trends. Genes differentially expressed in vitro between cell lines carrying or not the A allele could be applied to the transcriptional profile of 112 melanoma metastases to predict their responsiveness to therapy, suggesting that IRF5 genotype may influence immune responsiveness by affecting the intrinsic biology of melanoma. CONCLUSIONS:This study is the first to analyze associations between melanoma immune responsiveness and IRF5 polymorphism. The results support a common genetic basis which may underline the development of autoimmunity and melanoma immune responsiveness.
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Project description:The IRF5-SLE risk haplotype is associated with SLE disease severity. We hypothesized that neutrophils from healthy risk donors would carry a pathogenic gene signature compared to non-risk donors. To compare basal neutrophil gene signature between risk and non-risk healthy individuals, fresh whole blood was collected from healthy donors, and granulocytes were extracted from the remaining pellet following Ficoll purification. RNA-seq libraries were prepared from globin-reduced RNA extracted from the granulocytes using the Qiagen RNA preparation kit.
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Project description:BACKGROUND: Polymorphisms in the interferon regulatory factor 5 (IRF5) gene are associated with susceptibility to systemic lupus erythematosus, rheumatoid arthritis and other diseases through independent risk and protective haplotypes. Several functional polymorphisms are already known, but they do not account for the protective haplotypes that are tagged by the minor allele of rs729302. METHODS: Polymorphisms in linkage disequilibrium (LD) with rs729302 or particularly associated with IRF5 expression were selected for functional screening, which involved electrophoretic mobility shift assays (EMSAs) and reporter gene assays. RESULTS: A total of 54 single-nucleotide polymorphisms in the 5' region of IRF5 were genotyped. Twenty-four of them were selected for functional screening because of their high LD with rs729302 or protective haplotypes. In addition, two polymorphisms were selected for their prominent association with IRF5 expression. Seven of these twenty-six polymorphisms showed reproducible allele differences in EMSA. The seven were subsequently analyzed in gene reporter assays, and three of them showed significant differences between their two alleles: rs729302, rs13245639 and rs11269962. Haplotypes including the cis-regulatory polymorphisms correlated very well with IRF5 mRNA expression in an analysis based on previous data. CONCLUSION: We have found that three polymorphisms in LD with the protective haplotypes of IRF5 have differential allele effects in EMSA and in reporter gene assays. Identification of these cis-regulatory polymorphisms will allow more accurate analysis of transcriptional regulation of IRF5 expression, more powerful genetic association studies and deeper insight into the role of IRF5 in disease susceptibility.
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Project description:PURPOSE: Interferon regulation factor 5 (IRF5) is a member of the IRF family of transcription factors that control the transactivation of type I interferon system-related genes as well as the expression of several other genes involved in immune response. Here, we investigated its association with Behcet's disease (BD) in a well defined group of Chinese Han patients. METHODS: A total of 152 unrelated Chinese patients with BD and 149 healthy blood donors were genotyped for IRF5rs2280714 and rs752637 polymorphisms. Genomic DNA was isolated from peripheral blood mononuclear cells. Genotyping of each single nucleotide polymorphism (SNPs) was performed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). Allele and genotype frequencies of IRF5rs2280714 and rs752637 polymorphisms were compared between patients and controls using a two-sided chi(2) test. RESULTS: The results showed no significant difference concerning the frequency of the allele of rs2280714 and rs752637 polymorphisms between BD patients and the normal controls (p=0.647 and p=0.105, respectively). The frequencies of the genotype of rs2280714 and rs752637 were not different between BD patients and the normal controls (p=0.233 and, p=0.266, respectively). Clinical manifestation stratification analysis did not show any association of IRF5 polymorphisms with BD patients (p>0.05). CONCLUSIONS: Our study revealed that the rs2280714 and rs752637 SNPs were not associated with the susceptibility to BD. There was no association between the two polymorphisms of IRF5 and any extraocular clinical manifestations in BD.
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