Peripheral blood cellular dynamics of Rheumatoid arthritis treatment informs about efficacy of response to disease modifying drugs.
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE229449 | GEO | 2023/06/28
REPOSITORIES: GEO
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Project description:This microarray study was conducted along with SATORI study, the clinical trial evaluated 125 patients with active RA with an inadequate response to low dose of MTX. Patients were allocated to receive either Tocilizumab(TCZ) 8 mg/kg every 4 weeks (TCZ group) or MTX 8 mg/week (MTX/control group) for 24 weeks. Gene expression profiles (GEP) of 112 patients - 54 patients from TCZ group and 58 patients from MTX group - were obtained in this study.
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Project description:Methotrexate (MTX) efficacy in the treatment of rheumatoid arthritis (RA) is variable and unpredictable, resulting in a need to identify biomarkers to guide drug therapy. This study evaluates changes in the plasma metabolome associated with response to MTX in RA with the goal of understanding the metabolic basis for MTX efficacy towards the identification of potential metabolic biomarkers of MTX response.
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Project description:This microarray study was conducted along with SATORI study, the clinical trial evaluated 125 patients with active RA with an inadequate response to low dose of MTX. Patients were allocated to receive either Tocilizumab(TCZ) 8 mg/kg every 4 weeks (TCZ group) or MTX 8 mg/week (MTX/control group) for 24 weeks. Gene expression profiles (GEP) of 112 patients - 54 patients from TCZ group and 58 patients from MTX group - were obtained in this study. PB samples were collected directly into PAXGene tubes before and after the treatments. Total RNA was extracted using PAXGene Blood RNA Kit with the optimal on-column DNase digestion. Two-color microarray was used to directly compare the samples before versus after the treatment. Total RNA was amplified and amino allyl aRNA of the sample before/after treatments was further labeled with Cy3/Cy5. The labeled aRNAs (mixture of Cy3 and Cy5) was hybridized onto microarray slide. Dye swapping was done with each investigation to account for dye bias in microarray experiments.
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Project description:Differences in DNA methylation have been reported in B and T lymphocyte populations, including CD4+ T cells, isolated from rheumatoid arthritis (RA) patients when compared to healthy controls. CD4+ T cells are a heterogeneous cell type with subpopulations displaying distinct DNA methylation patterns. In this study, we investigated DNA methylation using reduced representation bisulfite sequencing in two CD4+ T cell populations (CD4+ memory and naïve cells) in three groups: newly diagnosed, disease modifying antirheumatic drugs (DMARD) naïve RA patients (N=11), methotrexate (MTX) treated RA patients (N=18), and healthy controls (N=9) matched for age, gender and smoking status. Analyses of these data revealed significantly more differentially methylated positions (DMPs) in CD4+ memory than in CD4+ naïve T cells (904 vs 19 DMPs) in RA patients compared to controls. The majority of DMPs (72%) identified in newly diagnosed and DMARD naïve RA patients with active disease showed increased DNA methylation (39 DMPs), whereas most DMPs (80%) identified in the MTX treated RA patients in remission displayed decreased DNA methylation (694 DMPs). Interestingly, we also found that about one third of the 101 known RA risk loci overlapped (+/- 500 kb) with the DMPs. Notably, introns of the UBASH3A gene harbour both the lead RA risk SNP and two DMPs in CD4+ memory T cells. Our results suggest that RA associated DNA methylation differences vary between the two T cell subsets, but are also influenced by RA characteristics such as disease activity, disease duration and/or MTX treatment.
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Project description:This research aims at assessing the m6A methylome in the RA peripheral blood mononuclear cells (PBMCs) and perform potential drug targets prediction analysis. Five RA samples and ten control samples were obtained from China-Japan Friendship Hospital. The various expression of m6A methylation and genes in RA and control group were compared with methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA sequencing (RNA-seq). Bioinformatics explorations were also made to explore the enriched biological roles and paths of the differentially expressed m6A methylation and genes. Potential drug targets prediction and validation were also constructed to provide potential therapeutic targets for RA. In total, 583 dysregulated m6A peaks, of which 295 were greatly upregulated and 288 were greatly downregulated, were identified. Similarly, 1570 differentially genes were acquired by RNA-seq, including 539 upregulated and 1031 downregulated. According to deeper joint exploration, the m6A methylation and mRNA expression degrees of 35 genes varied greatly, of which including 13 hyper-methylated as well as upregulated genes (hyper-up), 12 hyper-methylated and downregulated genes (hyper-down), 5 hypo-methylated as well as upregulated genes (hypo-up), and 5 hypo-methylated and downregulated genes (hypo-down) GO and KEGG explorations showed the enrichment of these distinct genes in “protein transport” “protein binding” and “lysosome”. In addition, the mRNA levels of TUBB2A, IGF2BP3, DYNC1I1 and FOSL1 were increased and consistent with the trend of our sequencing results. While after the treatment of TP and MTX, their mRNA levels were decreased. This research set up the transcriptional map of m6A in RA PBMCs and displayed the hidden association between RNA methylation alternation and associated genes in RA. The outcomes highlight the importance of m6A modification as a gene regulatory system in RA. Furthermore, TUBB2A, IGF2BP3, DYNC1I1 and FOSL1 might be potential therapeutic targets of TP and MTX during RA treatment.
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Project description:The joint disease rheumatoid arthritis (RA) is characterized by persistent synovitis, leading to cartilage damage, bone erosion, and ultimately impaired joint function. The disease affects 0.5 to 1.0% of adults in developed countries, and is three times more frequent in women than in men. A number of autoantibodies can be detected in RA patient’s serum targeting the patient’s own proteins. Several of these proteins, including rheumatoid factor, can also be detected in patients suffering from other autoimmune diseases, including the inflammatory bowel diseases (IBD). IBD and RA share several genetic risk logi, an altered gut microbiota, and environmental risk factors. Articular involvement is the most common extra-intestinal manifestation in patients diagnosed with IBD, with a prevalence between 17 to 39%. Additionally, methotrexate (MTX) is the most frequently prescribed immunosuppressive drug for RA and the second most for the IBD, indicating close similarities between the two diseases. We, therefore, characterized the protein content (the proteome) of the colon mucosa of gastrointestinal healthy RA patients, to investigate if we could detect IBD-related changes. The LC-MS/MS analysis was conducted as part of a previous study (ProteomeXChange submission PXD001608), enabling a comparison between the two datasets, containing the colon mucosal proteome of 11 RA patients, 10 IBD (ulcerative colitis) patients, and 10 controls. This data submission covers the triplicate proteome analysis of the colon mucosa of 11 gastrointestinal healthy RA patients.
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