RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis-Novel Targets for Therapy?
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ABSTRACT:
SUBMITTER: Vecellio M
PROVIDER: S-EPMC6335330 | biostudies-literature | 2018
REPOSITORIES: biostudies-literature
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RUNX3 and T-Bet in Immunopathogenesis of Ankylosing Spondylitis-Novel Targets for Therapy?
Vecellio Matteo M Cohen Carla J CJ Roberts Amity R AR Wordsworth Paul B PB Kenna Tony J TJ
Frontiers in immunology 20190110
Susceptibility to ankylosing spondylitis (AS) is polygenic with more than 100 genes identified to date. These include <i>HLA-B27</i> and the aminopeptidases (<i>ERAP1, ERAP2</i>, and <i>LNPEPS</i>), which are involved in antigen processing and presentation to T-cells, and several genes (<i>IL23R, IL6R, STAT3, JAK2, IL1R1/2, IL12B</i>, and <i>IL7R</i>) involved in IL23 driven pathways of inflammation. AS is also strongly associated with polymorphisms in two transcription factors, RUNX3 and T-bet ...[more]
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Project description:BACKGROUND We aimed to assess the potential association of runt-related transcription factor 3 (RUNX3) gene variants with ankylosing spondylitis (AS) susceptibility among Chinese Han people. MATERIAL AND METHODS Genotyping for RUNX3 variants was accomplished through polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in 115 AS patients and 102 healthy controls. Genotypes distributions of the polymorphisms in controls was assessed for their deviation from Hardy-Weinberg equilibrium (HWE). Moreover, odds ratio (OR) with 95% confidence interval (95%CI) was achieved using chi-square analysis to evaluate AS risk related to RUNX3 polymorphisms. Additionally, logistic regression analysis produced adjusted OR values. RESULTS Genotypes distribution of rs760805 and rs11249206 polymorphisms conformed to HWE in the control group (P>0.05). TT genotype of rs760805 appeared more frequently among AS cases than in controls (P=0.033), indicating its significant association with increased risk of AS onset (OR=2.309, 95%CI=1.069-4.892). The carriage of T allele in rs760805 also heightened AS incidence, in comparison to A allele (OR=1.578, 95%CI=1.075-2.316, P=0.020). Moreover, the carriage of AT+TT genotype in rs760805 and TT genotype in rs11249206 obviously increased risk of AS onset (OR=2.585, 95%CI=1.062-6.288). CONCLUSIONS RUNX3 rs760805 polymorphism can contribute to AS incidence in Chinese Han people. The interaction of the 2 polymorphisms may be a risk factor for AS.
| S-EPMC7212810 | biostudies-literature
Project description:Objectives:To explore the functions of RUNX3 single nucleotide polymorphisms (SNPs) associated with ankylosing spondylitis (AS). Methods:Individual SNP associations were evaluated in 4230 UK cases. Their effects on transcription factor (TF) binding, transcription regulation, chromatin modifications, gene expression and gene interactions were tested by database interrogation, luciferase reporter assays, electrophoretic mobility gel shifts, chromatin immunoprecipitation and real-time PCR. Results:We confirmed the independent association of AS with rs4265380, which was robust (P=4.7×10-6) to conditioning on another nearby AS-associated RUNX3 SNP (rs4648889). A RUNX3 haplotype incorporating both SNPs was strongly associated with AS (OR 6.2; 95%?CI 3.1 to 13.2, P=1.4×10-8). In a large UK cohort, rs4265380 is associated with leucocyte counts (including monocytes). RUNX3 expression is lower in AS peripheral blood mononuclear cells than healthy controls (P<0.002), independent of rs4265380 genotype. Enhancer function for this RUNX3 region was suggested by increased luciferase activity (approximately tenfold; P=0.005) for reporter constructs containing rs4265380. In monocytes, there was differential allelic binding of nuclear protein extracts to a 50?bp DNA probe containing rs4265380 that was strongly augmented by lipopolysaccharide activation. TF binding also included the histone modifier p300. There was enrichment for histone modifications associated with active enhancer elements (H3K27Ac and H3K79Me2) that may be allele dependent. Hi-C database interrogation showed chromosome interactions of RUNX3 bait with the nearby RP4-799D16.1 lincRNA. Conclusions:The association of AS with this RUNX3 regulatory region involves at least two SNPs apparently operating in different cell types. Monocytes may be potential therapeutic targets in AS.
| S-EPMC5845418 | biostudies-literature
Project description:ObjectiveTo investigate the functional consequences of the single-nucleotide polymorphism rs4648889 in a putative enhancer upstream of the RUNX3 promoter associated with susceptibility to ankylosing spondylitis (AS).MethodsUsing nuclear extracts from Jurkat cells and primary human CD8+ T cells, the effects of rs4648889 on allele-specific transcription factor (TF) binding were investigated by DNA pull-down assay and quantitative mass spectrometry (qMS), with validation by electrophoretic mobility shift assay (EMSA), Western blotting of the pulled-down eluates, and chromatin immunoprecipitation (ChIP)-quantitative polymerase chain reaction (qPCR) analysis. Further functional effects were tested by small interfering RNA knockdown of the gene for interferon regulatory factor 5 (IRF5), followed by reverse transcription-qPCR (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) to measure the levels of IFNγ messenger RNA (mRNA) and protein, respectively.ResultsIn nuclear extracts from CD8+ T cells, results of qMS showed that relative TF binding to the AS-risk A allele of rs4648889 was increased 3.7-fold (P < 0.03) for Ikaros family zinc-finger protein 3 (IKZF3; Aiolos) and components of the NuRD complex, including chromodomain helicase DNA binding protein 4 (CHD4) (3.6-fold increase; P < 0.05) and retinoblastoma binding protein 4 (RBBP4) (4.1-fold increase; P < 0.03). In contrast, IRF5 bound significantly more to the AS-protective G allele compared to the AS-risk A allele (fold change 8.2; P = 0.003). Validation with Western blotting, EMSA, and ChIP-qPCR confirmed the differential allelic binding of IKZF3, CHD4, RBBP4, and IRF5. Silencing of IRF5 in CD8+ T cells increased the levels of IFNγ mRNA as measured by RT-qPCR (P = 0.03) and IFNγ protein as measured by ELISA (P = 0.02).ConclusionThese findings suggest that the association of rs4648889 with AS reflects allele-specific binding of this enhancer-like region to certain TFs, including IRF5, IKZF3, and members of the NuRD complex. IRF5 may have crucial influences on the functions of CD8+ lymphocytes, a finding that could reveal new therapeutic targets for the management of AS.
| S-EPMC8251554 | biostudies-literature
Project description:BackgroundAnkylosing spondylitis (AS) is a chronic inflammatory disease affecting the spine and sacroiliac joints. Recent genetic studies suggest certain plasma proteins may play a causal role in AS development. This study aims to identify and characterize these proteins using Mendelian randomization (MR) and colocalization analyses.MethodsPlasma protein data were obtained from recent publications in Nature Genetics, integrating data from five previous GWAS datasets, including 738 cis-pQTLs for 734 plasma proteins. GWAS summary data for AS were sourced from IGAS and other European cohorts. MR analyses were conducted using "TwoSampleMR" to assess causal links between plasma protein levels and AS. Colocalization analysis was performed with the coloc R package to identify shared genetic variants. Sensitivity analyses and protein-protein interaction (PPI) network analyses were conducted to validate findings and explore therapeutic targets. We performed Phenome-wide association study (PheWAS) to examine the potential side effects of drug protein on AS treatment.ResultsAfter FDR correction, eight significant proteins were identified: IL7R, TYMP, IL12B, CCL8, TNFAIP6, IL18R1, IL23R, and ERAP1. Elevated levels of IL7R, IL12B, CCL8, IL18R1, IL23R, and ERAP1 increased AS risk, whereas elevated TYMP and TNFAIP6 levels decreased AS risk. Colocalization analysis indicated that IL23R, IL7R, and TYMP likely share causal variants with AS. PPI network analysis identified IL23R and IL7R as potential new therapeutic targets.ConclusionsThis study identified eight plasma proteins with significant associations with AS risk, suggesting IL23R, IL7R, and TYMP as promising therapeutic targets. Further research is needed to explore underlying mechanisms and potential for drug repurposing.
| S-EPMC11341372 | biostudies-literature
Project description:Previous studies show that endoplasmic reticulum-associated aminopeptidase (ERAP1/ERAP2) and runt-related transcription factor 3 (RUNX3) gene polymorphisms are associated with AS (ankylosing spondylitis) in European Caucasians. However, contradictory results were reported in different Asian populations. The purpose of this study was to determine whether eleven candidate single nucleotide polymorphisms (SNPs) in ERAP1/ERAP2 and six in RUNX3 genes confer susceptibility to AS with or without acute anterior uveitis (AAU) [AS+ AAU+ or AS+ AAU- ] in Chinese Han. Therefore, a case-control association study was performed in 882 AS+ AAU- , 884 AS+ AAU+ and 1727 healthy controls. Genotyping was performed using the iPLEXGold genotyping assay. A meta-analysis was performed to assess the association of polymorphisms of ERAP1 with AS susceptibility in Asian populations. No association was found between SNPs of ERAP1/ERAP2/RUNX3 and susceptibility of AS with or without AAU. A case-control study between patients with human leucocyte antigen HLA-B27-positive and healthy controls also failed to demonstrate an association of the tested SNP with AS with or without AAU. Moreover, a meta-analysis showed that there was no association of rs30187, rs27037, rs27980, rs27434 and rs27582 in ERAP1 with AS in Chinese Han. Taken together, 17 SNPs in ERAP1/ERAP2 and RUNX3 genes did not confer disease susceptibility to AS in Chinese Han.
| S-EPMC6038008 | biostudies-literature
Project description:Ankylosing spondylitis (AS) is a chronic autoinflammatory disease that affects the spine and sacroiliac joints. Regarding its etiology, although HLA-B27 is known to be the strongest genetic factor of AS, much evidence suggests the potential contribution of non-MHC genes to the susceptibility to AS. Most of these non-MHC genes have been discovered in non-Asian populations; however, just some of them have been validated in Koreans. In this study, we aimed to identify additional AS-associated single-nucleotide polymorphism (SNP) candidates by replicating the candidate SNPs in Korean AS patients and healthy controls. For this, we selected three SNPs (rs11249215 in RUNX3, rs6556416 in IL12B, and rs8070463 in TBKBP1), which were previously reported as risk factors of AS but have not been studied in Koreans, and performed genotyping assays using a total of 1138 Korean samples (572 AS patients and 566 healthy controls). Of the three SNP candidates, one SNP in RUNX3 (rs11249215) was significantly associated with the risk of AS (odds ratio, 1.31; 95% confidence interval, 1.02 to 1.68, p = 0.03). These results will be helpful in elucidating the pathogenesis of AS and may be useful for developing AS risk prediction models in Koreans.
| S-EPMC5478709 | biostudies-literature
Project description:BackgroundAnkylosing Spondylitis (AS) is a chronic inflammatory disorder which can lead to considerable pain and disability. Mendelian randomization (MR) has been extensively applied for repurposing licensed drugs and uncovering new therapeutic targets. Our objective is to pinpoint innovative therapeutic protein targets for AS and assess the potential adverse effects of druggable proteins.MethodsWe conducted a comprehensive proteome-wide MR study to assess the causal relationships between plasma proteins and the risk of AS. The plasma proteins were sourced from the UK Biobank Pharma Proteomics Project (UKB-PPP) database, encompassing GWAS data for 2,940 plasma proteins. Additionally, GWAS data for AS were extracted from the R9 version of the Finnish database, including 2,860 patients and 270,964 controls. The colocalization analysis was executed to identify shared causal variants between plasma proteins and AS. Finally, we examined the potential adverse effects of druggable proteins for AS therapy by conducting a phenome-wide association study (PheWAS) utilizing the extensive Finnish database in version R9, encompassing 2,272 phenotypes categorized into 46 groups.ResultsThe findings revealed a positive genetic association between the predicted plasma levels of six proteins and an elevated risk of AS, while two proteins exhibited an inverse association with AS risk (P fdr < 0.05). Among these eight plasma proteins, colocalization analysis identified AIF1, TNF, FKBPL, AGER, ALDH5A1, and ACOT13 as shared variation with AS(PPH3+PPH4>0.8), suggesting that they represent potential direct targets for AS intervention. Further phenotype-wide association studies have shown some potential side effects of these six targets (P fdr < 0.05).ConclusionOur investigation examined the causal connections between six plasma proteins and AS, providing a comprehensive understanding of potential therapeutic targets.
| S-EPMC10985162 | biostudies-literature
Project description:BackgroundAnkylosing spondylitis (AS) is a chronic inflammatory disease known for causing pain, stiffness, and reduced mobility in the axial skeleton. Adalimumab, a tumor necrosis factor (TNF) inhibitor, has emerged as a promising therapeutic option for AS.MethodsThis systematic review involved a comprehensive search of randomized controlled trials related to AS treatment, conducted in major databases such as MEDLINE, Google Scholar, and PubMed. The search terms encompassed ankylosing spondylitis, adalimumab, methotrexate, other non-biologic DMARDs, glucocorticoids, NSAIDs, and analgesics. A total of 14 randomized controlled trials with 4,500 participants were included in the review.ResultsThe review's results revealed that adalimumab demonstrated notable superiority when compared to a placebo. It effectively reduced disease activity, improved physical function, and lowered inflammatory markers such as C-reactive protein and erythrocyte sedimentation rate. Adalimumab demonstrated a favorable safety profile, with adverse events comparable to those observed with placebo.ConclusionBased on the results, adalimumab is deemed an effective treatment for AS, showcasing its potential as a first-line therapeutic option. Notably, no significant increase in adverse events was observed compared to placebo. However, the conclusion emphasizes the need for further studies with extended follow-up durations to ascertain the long-term efficacy and safety of adalimumab in AS management. This systematic review provides valuable insights supporting the use of adalimumab in the treatment of AS and underscores the importance of ongoing investigations into its long-term effects to optimize its clinical utilization in AS patients.
| S-EPMC11340288 | biostudies-literature
Project description:BackgroundSusceptibility to and severity of ankylosing spondylitis (AS) are largely genetically determined. PPARGC1B, RUNX3 and TBKBP1 have recently been found to be associated with AS in patients of western European descent. Our purpose is to examine the influence of PPARGC1B, RUNX3 and TBKBP1 polymorphisms on the susceptibility to and the severity of ankylosing spondylitis in Chinese ethnic majority Han population.MethodsBlood samples are drawn from 396 AS patients and 404 unrelated healthy controls. All the patients and the controls are Han Chinese and the patients are HLA-B27 positive. The AS patients are classified based on the severity of the disease. Twelve tag single nucleotide polymorphisms (tagSNPs) in PPARGC1B, RUNX3 and TBKBP1 are selected and genotyped. Frequencies of different genotypes and alleles are analyzed among the different severity AS patients and the controls.ResultsAfter Bonferroni correction, the rs7379457 SNP in PPARGC1B shows significant difference when comparing all AS patients to controls (p?=?0.005). This SNP also shows significant difference when comparing normal AS patients to controls (p?=?0.002). The rs1395621 SNP in RUNX3 shows significant difference when comparing severe AS patients to controls (p?=?0.007). The rs9438876 SNP in RUNX3 shows significant difference when comparing normal AS patients to controls (p?=?0.007). The rs8070463 SNP in TBKBP1 shows significant difference in genotype distribution when comparing severe AS patients to controls (p?=?0.003).ConclusionsThe rs7379457 SNP in PPARGC1B is related to susceptibility to AS in Chinese Han population. The rs7379457 SNP in PPARGC1B, the rs1395621 and rs9438876 SNPs in RUNX3, and the rs8070463 SNP in TBKBP1 are related to the severity of AS in Chinese Han population.
| S-EPMC3630117 | biostudies-literature
Project description:We have compared synovial biopsies from ankylosing spondylitis and undifferentiated spondylitis patients with healthy controls and osteoarthritis patients Objective: In spondylarthropies, whole-genome gene expression profiling studies have been limited to peripheral blood to date. By undertaking a study in knee synovial biopsies from spondylarthropy (SpA) and ankylosing spondylitis (AS) patients we aimed to identified joint-specific candidate genes and pathways. These pathways may mediate systemic inflammation driven joint damaging processes and more specifically, the osteoproliferation that is characteristic of these conditions. Methods: RNA was extracted from six seronegative SpA, two AS, three osteoarthritis (OA) and four normal control knee synovial biopsies. Whole genome expression profiling was undertaken using the Illumina DASL system, which assays 24000 cDNA probes. Differentially expressed candidate genes were then validated using quantitative PCR and immunohistochemistry. Results: 416 differentially expressed genes were identified that clearly delineated between AS/SpA and control groups. Pathway analysis showed altered gene-expression in oxidoreductase activity, osteoblast activity, B-cell associated, matrix catabolic, and metabolic pathways. The inflammatory mediator, MMP3, was strongly upregulated in AS/SpA samples and the Wnt pathway inhibitors DKK3 and Kremen1 were downregulated. Conclusion: Pathways mediating both systemic inflammation as well as local tissue changes were identified. This suggests initial systemic inflammation in spondylarthropies transfers to and persists in the local joint environment, subsequently mediating changes in genes directly involved in the destructive tissue remodelling. Fifteen knee synovial biopsy tissue samples consisting of six seronegative spondyloarthropy (SpA), two ankylosing spondylitis (AS), three osteoarthritis (OA) and four normal control biopsies were obtained from the Synovial Tissue Bank at the Repatriation General Hospital in Adelaide, South Australia with the appropriate ethical approval (Supplementary Table 1). All patients provided informed written consent.
2012-12-01 | E-GEOD-41038 | biostudies-arrayexpress