Polymorphisms In Interferon Regulatory Factor Research Articles

Genetic Polymorphism of Interferon Regulatory Factor 5 Gene in Egyptian Children with Systemic Lupus Erythematosus

Genetic Polymorphism of Interferon Regulatory Factor 5 Gene in Egyptian Children with Systemic Lupus Erythematosus

Retraction: Genetic Polymorphism of Interferon Regulatory Factor 5 (IRF5) Correlates with Allograft Acute Rejection of Liver Transplantation.

Retraction: Genetic Polymorphism of Interferon Regulatory Factor 5 (IRF5) Correlates with Allograft Acute Rejection of Liver Transplantation.

Disrupted IRF6-NME1/2 Complexes as a Cause of Cleft Lip/Palate

Mutations and common polymorphisms in interferon regulatory factor 6 (IRF6) are associated with both syndromic and nonsyndromic forms of cleft lip/palate (CLP). To date, much of the focus on this transcription factor has been on identifying its direct targets and the gene regulatory network in which it operates. Notably, however, IRF6 is found predominantly in the cytoplasm, with its import into the nucleus tightly regulated like other members of the IRF family. To provide further insight into the role of IRF6 in the pathogenesis of CLP, we sought to identify direct IRF6 protein interactors using a combination of yeast 2-hybrid screens and co-immunoprecipitation assays. Using this approach, we identified NME1 and NME2, well-known regulators of Rho-type GTPases, E-cadherin endocytosis, and epithelial junctional remodeling, as bona fide IRF6 partner proteins. The NME proteins co-localize with IRF6 in the cytoplasm of primary palatal epithelial cells in vivo, and their interaction with IRF6 is significantly enhanced by phosphorylation of key serine residues in the IRF6 C-terminus. Furthermore, CLP associated IRF6 missense mutations disrupt the ability of IRF6 to bind the NME proteins and result in elevated activation of Rac1 and RhoA, compared to wild-type IRF6, when ectopically expressed in 293T epithelial cells. Significantly, we also report the identification of 2 unique missense mutations in the NME proteins in patients with CLP (NME1 R18Q in an IRF6 and GRHL3 mutation-negative patient with van der Woude syndrome and NME2 G71V in a patient with nonsyndromic CLP). Both variants disrupted the ability of the respective proteins to interact with IRF6. The data presented suggest an important role for cytoplasmic IRF6 in regulating the availability or localization of the NME1/2 complex and thus the dynamic behavior of epithelia during lip/palate development.

Association between genetic polymorphisms in interferon regulatory factor 5 (IRF5) gene and Malaysian patients with Crohn's disease.

The study aimed to investigate the association between the interferon regulatory factor 5 (IRF5) gene polymorphisms and the onset of Crohn's disease (CD) in a Malaysian cohort. Genomic DNA was extracted from blood samples collected from 91 CD patients and 100 healthy individuals via a conventional phenol-chloroform extraction method. Screening of the four target single nucleotide polymorphisms (SNPs), including rs3807306, rs4728142, rs10954213 and rs11770589 was carried out in a real-time polymerase chain reaction (PCR) thermal cycler using TaqMan genotyping assay. The genetic data obtained was subsequently subjected to statistical analysis to relate the SNPs to the onset of CD in the Malaysian population. The genotyping assay and data were further validated selectively by conventional PCR amplification of the SNP sites and DNA sequencing. The rs3807306 G allele was a risk factor for CD (OR 2.3630, P = 0.00004), whereas the homozygous T genotype was protective against the disease (OR 0.2038, P = 0.00004). The heterozygous A/G genotype of rs10954213 was significantly associated with CD (OR 4.319, P = 0.0377). On the other hand, the homozygous A and heterozygous A/G genotypes of the rs11770589 were significant in the controls (OR 0.4242, P = 0.0166) and patients (OR 2.000, P = 0.0179), respectively. In the ethnic-stratification analysis, the rs11770589 homozygous A genotype was protective in Indians (OR 0.1551, P = 0.0112). IRF5 gene polymorphisms may play a role in the development of CD in the Malaysian population.

Association of functional polymorphisms in interferon regulatory factor 2 (IRF2) with susceptibility to systemic lupus erythematosus: a case-control association study.

Interferon regulatory factor 2 (IRF2) negatively regulates type I interferon (IFN) responses, while it plays a role in induction of Th1 differentiation. Previous linkage and association studies in European-American populations suggested genetic role of IRF2 in systemic lupus erythematosus (SLE); however, this observation has not yet been confirmed. No studies have been reported in the Asian populations. Here we investigated whether IRF2 polymorphisms contribute to susceptibility to SLE in a Japanese population. Association study of 46 IRF2 tag single nucleotide polymorphisms (SNPs) detected association of an intronic SNP, rs13146124, with SLE. When the association was analyzed in 834 Japanese patients with SLE and 817 healthy controls, rs13146124 T was significantly increased in SLE compared with healthy controls (dominant model, P = 5.4×10−4, Bonferroni-corrected P [Pc] = 0.026, odds ratio [OR] 1.48, 95% confidence interval [CI] 1.18–1.85). To find causal SNPs, resequencing was performed by next-generation sequencing. Twelve polymorphisms in linkage disequilibrium with rs13146124 (r2: 0.30–1.00) were identified, among which significant association was observed for rs66801661 (allele model, P = 7.7×10−4, Pc = 0.037, OR 1.53, 95%CI 1.19–1.96) and rs62339994 (dominant model, P = 9.0×10−4, Pc = 0.043, OR 1.46, 95%CI 1.17–1.82). The haplotype carrying both of the risk alleles (rs66801661A–rs62339994A) was significantly increased in SLE (P = 9.9×10−4), while the haplotype constituted by both of the non-risk alleles (rs66801661G–rs62339994G) was decreased (P = 0.0020). A reporter assay was carried out to examine the effect of the IRF2 haplotypes on the transcriptional activity, and association of the IRF2 risk haplotype with higher transcriptional activity was detected in Jurkat T cells under IFNγ stimulation (Tukey's test, P = 1.2×10−4). In conclusion, our observations supported the association of IRF2 with susceptibility to SLE, and the risk haplotype was suggested to be associated with transcriptional activation of IRF2.

Genetic polymorphism of interferon regulatory factor 5 (IRF5) correlates with allograft acute rejection of liver transplantation.

BackgroundAlthough liver transplantation is one of the most efficient curative therapies of end stage liver diseases, recipients may suffer liver graft loss opst-operation. IRF-5, a member of Interferon Regulatory Factors, functions as a key regulator in TLR4 cascade, and is capable of inducing inflammatory cytokines. Although TLR4 has been proved to contribute to acute allograft rejection, including after liver transplantation, the correlation between IRF5 gene and acute rejection has not been elucidated yet.MethodsThe study enrolled a total of 289 recipients, including 39 females and 250 males, and 39 recipients developed acute allograft rejection within 6 months post-transplantation. The allograft rejections were diagnosed by liver biopsies. Genome DNA of recipients was extracted from pre-operative peripheral blood. Genotyping of IRF-5, including rs3757385, rs752637 and rs11761199, was performed, followed by SNP frequency and Hardy-Weinberg equilibrium analysis.ResultsThe genetic polymorphism of rs3757385 was found associated with acute rejection. G/G homozygous individuals were at higher risk of acute rejection, with a P value of 0.042 (OR = 2.34 (1.07–5.10)).ConclusionsIRF5, which transcriptionally activates inflammatory cytokines, is genetically associated with acute rejection and might function as a risk factor for acute rejection of liver transplantations.

Association between polymorphism of IRF6 rs2235371 locus and nonsyndromic cleft lip with or without cleft palate

To assess the association between polymorphism of interferon regulatory factor 6 (IRF6) gene rs2235371 locus and nonsyndromic cleft lip with or without cleft palate in Chinese population. Blood samples from 106 patients and their parents and 129 controls and their parents were collected. The polymorphism of IRF6 rs2235371 locus was determined with PCR-restriction fragment length polymorphism (PCR-RFLP) method. Case-control analysis, transmission disequilibrium test(TDT), haplotype-based haplotype relative risk analysis (HHRR) and family-based association test (FBAT) were carried out. By case-control analysis, no significant difference was found in the frequencies of GG, GA and AA genotypes of rs2235371 locus between the patient group and control group (P> 0.05), but there was a significant difference in allelic frequencies (P< 0.05). There was also a significant difference in genotype and gene frequencies of rs2235371 variant between family members from cleft lip only group and control group. However, in cleft lip with cleft palate group, no such difference was observed. TDT analysis suggested a linkage in the presence of disequilibrium (chi-square=5.56, P=0.024). Results of HHRR analysis (chi-square=5.115, P=0.024) and FBAT (Z=2.218, P=0.027) also indicated an association between IRF6 rs2235371 variant and the risk of NSCL with or without cleft palate. Genetic polymorphism of IRF6 gene rs2235371 locus is associated with NSCL with or without cleft palate.

Association of IRF5 Polymorphisms with Susceptibility to Hemophagocytic Lymphohistiocytosis in Children

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome and has a varied genetic background. The polymorphism of interferon regulatory factor 5 gene (IRF5) was reported to be associated with susceptibility to macrophage activation syndrome. IRF5 acts as a master transcription factor in the activation of pro-inflammatory cytokines. We assessed associations of IRF5 gene polymorphisms with susceptibility to secondary HLH. Three IRF5 single nucleotide polymorphisms (rs729302, rs2004640, and rs2280714) were genotyped using TaqMan assays in 82 secondary HLH patients and 188 control subjects. There was a significant association of the GT/TT genotype at rs2004640 with secondary HLH susceptibility (p < 0.01). The IRF5 haplotype (rs729302 A, rs2004640 T, and rs2280714 T) was associated with secondary HLH susceptibility (p < 0.01). These findings indicate that IRF5 is a genetic factor influencing the susceptibility to secondary HLH and that the IRF5-associated immune response contributes to the pathogenesis of HLH.

Polymorphisms in interferon regulatory factor 7 reduce interferon-α responses of plasmacytoid dendritic cells to HIV-1.

Recognition of HIV-1 ssRNA by Toll-like receptor 7 induces the production of the pro-inflammatory cytokines that may contribute to the systemic immune activation associated with HIV-1 disease progression. Here, we describe a novel association between polymorphisms in interferon regulatory factor 7 (IRF7), a master regulator of interferon-α (IFN-α), and the ability of plasmacytoid dendritic cells to produce IFN-α in response to HIV-1. IRF7 polymorphisms may, therefore, affect the ability of individuals to respond to HIV-1 and modulate HIV-1 disease progression.

Association Between IRF-5 Polymorphisms and Risk of Acute Coronary Syndrome

Previous studies suggested that genetic polymorphisms in interferon regulatory factor 5 (IRF-5) are implicated in the susceptibility to a range of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. Recently, IRF-5 has been implicated in inflammatory processes that are associated with excessive remodeling and atherosclerosis. Our purpose was to investigate the association between the IRF-5 polymorphisms and the risk of acute coronary syndrome (ACS) in a Chinese population. The 5 bp indel (insertion/deletion) (CGGGG) polymorphism, located 64 bp upstream of the alternative exon 1a of IRF-5 gene, and the deletion of 30 bp in exon 6 of IRF-5 gene were analyzed among 148 patients with ACS and 246 controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism strategy and direct sequencing. The frequencies of (CGGGG)(3)(CGGGG)(4) genotype and (CGGGG)(4) allele in ACS patients were significantly higher than those in control subjects (p = 0.018, odds ratio [OR] = 1.76, 95% confidence interval [CI]: 1.10-2.81; p = 0.028, OR = 1.62, 95% CI: 1.05-2.50, respectively). However, no significant relationship between the 30 bp exon 6 polymorphism of the IRF-5 gene and the risk of ACS was observed (p = 0.770, OR = 0.96, 95% CI: 0.72-1.28). The 5 bp indel (CGGGG) polymorphism of the IRF-5 gene may be associated with susceptibility to ACS.

Association between the rs2004640 functional polymorphism of interferon regulatory factor 5 and systemic lupus erythematosus: a meta-analysis

The aim of this study is to determine whether the functional interferon regulatory factor 5 (IRF5) polymorphism, rs2004640, confers susceptibility to systemic lupus erythematosus (SLE) in multiple ethic populations. A meta-analysis was conducted on the T allele of the IRF5 rs2004640 polymorphism and 12 studies were included in the meta-analysis. Meta-analysis revealed an association between SLE and the IRF5 rs2004640 T allele in all subjects without inter-study heterogeneity (OR 1.429, 95% CI 1.359-1.503, P < 0.001). The IRF5 rs2004640 T allele was significantly associated with SLE in European and Asians. The Asian population had a much lower prevalence of the T allele (34.4%) than any other population studied. and Europeans had the highest frequency of the IRF5 rs2004640 T allele (51.8%). In conclusion, this meta-analysis confirms that the IRF5 rs2004640 polymorphism is associated with SLE susceptibility in different ethnic groups, and that its prevalence is ethnicity dependent.