Differential expression of IBD susceptibility and IL23R associated pathway genes during ongoing anti-TNF therapy (anti-TNF non-responder vs anti-TNF responder)
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE111761 | GEO | 2018/05/01
REPOSITORIES: GEO
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Project description:Differential expression of IBD susceptibility and IL23R associated pathway genes during ongoing anti-TNF therapy (anti-TNF non-responder vs anti-TNF responder)
| PRJNA438079 | ENA
Project description:Steady state mice were categorized as responders and non-responders to melanoma immunotherapy treatment.
| PRJEB61041 | ENA
Project description:The objective of this study was to identify pre-treatment colonic gene expression patterns in patients with inflammatory bowel disease (Ulcerative Colitis and colonic Crohn’s disease) that are predictive of a good versus poor response to treatment with the bioloic anti-TNFa. By identifying key pathways that are altered in responders versus non-responders we also aimed to propose novel targets for therapy. Pre-treatment colonic endoscopic biopsies were collected in RNAlater from 22 patients (14 CD and 8 UC) who were starting anti-TNFa therapy. RNA was extracted using RNeasy columns (Qiagen) and quantified by Qubit (Life Technologies). 0.5ng RNA was used to prepare uniquely indexed cDNA QIAseq UPX 3’ Transcriptome libraries according to manufacturer’s instructions (Qiagen). Libraries were quantified and quality-controlled using the QIAseq Library Quant Assay Kit and tapestation analysis and sequenced on the Miseq and Nextseq Illumina platforms using the illumina sequencing primer and PhiX 15% to a depth of 1-3milion reads/sample. Read numbers were set as 101 bp (R1) x 51 bp (R2). Fastq files were obtained through BaseSpace and reads de-multiplexed, aligned to human genome GRCh38, quantified and normalised by the TPM method using the CLC Genomics Workbench (Qiagen). The following differential expression procedure was performed for participants classified as responders, partial responders or non-responders according to their endoscopic presentation 12 weeks after therapy. For UC patients the Mayo score was used: Responders Mayo= 0, Partial responders 1<= Mayo <3 and Non Responders Mayo >=3. For CD patients % reduction in the SES-CD score was used: Responders >=50% of SES-CD, Partial responders 50%<SES-CD<75%, Non responders SES-CD > 75%. Normalised values were log-transformed with a pseudocount of 1 added. Transcripts with < 1 transformed count in any sample were excluded from further analysis, as were transcripts with low variance (defined as less than 10% unique counts across both conditions and greater than a 19:1 ratio of the most frequent count to the second most frequent across both conditions). Differential expression analysis between conditions was conducted with the limma package. Library size was estimated using reduced maximum likelihood estimator with 500 iterations. Initial fitting was performed using a robust M-estimation, and moderated test statistics computed by empirical Bayes. A FDR corrected p value <0.05 was considered and filtered for further downstream data analysis. Partial least squares discriminant analysis (PLS-DA) modelling was performed on these genes to calculate their variable Importance in Projection (VIP) score. To understand the biological significance and pathways represented in the DEGS, we also performed enrichment analysis using the DAVID Gene Functional Classification Tool (REF I,II). Finally, strongest indicators of response were predicted by Random Forest Area Under the Curve (AUC) analysis.
2022-12-31 | E-MTAB-9944 | biostudies-arrayexpress
Project description:Expression profiles of anti-TNF responders were compared to profiles of anti-TNF non-responders in order to identify an expression signature for anti-TNF response In total 42 patients were treated with anti-TNF. RNA was isoloated from white blood cells and anti-TNF responders (n=18) were compared to nonresponders (n=24) regarding expression profiles
2012-01-01 | E-GEOD-33377 | biostudies-arrayexpress
Project description:Inflammatory bowel disease (IBD) is a chronic gastrointestinal condition characterized by severe gut inflammation, commonly presenting as Crohn's disease, ulcerative colitis or categorized as IBD- unclassified. While various treatments have demonstrated efficacy in adult IBD patients, the advent of anti-TNF therapies has significantly revolutionized treatment outcomes and clinical management. These therapies have played a pivotal role in achieving clinical and endoscopic remission, promoting mucosal healing, averting disease progression, and diminishing the necessity for surgery. Nevertheless, not all patients exhibit positive responses to these therapies, and some may experience a loss of responsiveness over time. This review aims to present a comprehensive examination of predictive biomarkers for monitoring the therapeutic response to anti-TNF therapy in IBD patients. It will explore their limitations and clinical utilities, paving the way for a more personalized and effective therapeutic approach.
| S-EPMC10943853 | biostudies-literature
Project description:Expression profiles of anti-TNF responders were compared to profiles of anti-TNF non-responders in order to identify an expression signature for anti-TNF response
2012-01-01 | GSE33377 | GEO
Project description:Background and aimsInflammatory Bowel Diseases (IBD) are chronic inflammatory conditions influenced heavily by environmental factors. DNA methylation is a form of epigenetic regulation linking environmental stimuli to gene expression changes and inflammation. Here, we investigated how DNA methylation of the TNF promoter differs between inflamed and uninflamed mucosa of IBD patients, including anti-TNF responders and non-responders.MethodsWe obtained mucosal biopsies from 200 participants (133 IBD and 67 controls) and analyzed TNF promoter methylation using bisulfite sequencing, comparing inflamed with uninflamed segments, in addition to paired inflamed/uninflamed samples from individual patients. We conducted similar analyses on purified intestinal epithelial cells from bowel resections. We also compared TNF methylation levels of inflamed and uninflamed mucosa from a separate cohort of 15 anti-TNF responders and 17 non-responders. Finally, we sequenced DNA methyltransferase genes to identify rare variants in IBD patients and functionally tested them using rescue experiments in a zebrafish genetic model of DNA methylation deficiency.ResultsTNF promoter methylation levels were decreased in inflamed mucosa of IBD patients and correlated with disease severity. Isolated IECs from inflamed tissue showed proportional decreases in TNF methylation. Anti-TNF non-responders showed lower levels of TNF methylation than responders in uninflamed mucosa. Our sequencing analysis revealed two missense variants in DNMT1, one of which had reduced function in vivo.ConclusionsOur study reveals an association of TNF promoter hypomethylation with mucosal inflammation, suggesting that IBD patients may be particularly sensitive to inflammatory environmental insults affecting DNA methylation. Together, our analyses indicate that TNF promoter methylation analysis may aid in the characterization of IBD status and evaluation of anti-TNF therapy response.
| S-EPMC10871362 | biostudies-literature
Project description:Objectives: This study was undertaken to understand the mechanistic basis of response to anti-TNF therapies and determine if transcriptomic changes in the synovium are reflected in peripheral protein markers. Methods: Synovial tissue from 46 RA patients was profiled with RNA sequencing before and 12 weeks after treatment with anti-TNF therapies. Pathway and gene signature analyses were performed on RNA expression profiles of synovial biopsies to identify mechanisms that could discriminate among EULAR good, moderate and non-responders. Serum proteins encoded by synovial genes differentially expressed between EULAR response groups were measured in the same patients. Results: The gene signatures were able to predict good responder patients and pathway analysis identified elevations in immune pathways including chemokine signaling, Th1 and Th2 cell differentiation, and Toll-like receptor signaling uniquely in good responders. These inflammatory pathways were correspondingly down-modulated by anti-TNF therapy only in good responders. Based on cell signature analysis, lymphocyte, myeloid and fibroblast cell populations were elevated in good responders relative to non-responders, consistent with the increased inflammatory pathways. Cell signatures which decreased following anti-TNF treatment were predominately associated with lymphocytes and fewer were associated with myeloid and fibroblast populations. Following anti-TNF treatment and only in good responders, several peripheral inflammatory proteins decreased consistent with corresponding synovial gene changes. Conclusions: Collectively, these data suggest that RA patients with robust responses to anti-TNF therapies are characterized at baseline by immune pathway activation, which decreases following anti-TNF treatment. Understanding mechanisms that define patient responsiveness to anti-TNF may assist in development of predictive markers of patient response and earlier treatment options.
2022-06-06 | GSE198520 | GEO
Project description:The antitumour necrosis factor (TNF) medications, adalimumab and infliximab, play an important role in the management of both Crohn's disease and ulcerative colitis. For those in whom anti-TNF is effective, the therapy is associated with fewer symptoms, improved quality of life and disease and surgery-free survival. Unfortunately, up to 30% of patients will fail to respond to anti-TNF drugs while up to 50% of those who do see an initial response will lose response at some point. The introduction of drug monitoring for anti-TNFs, including drug level and antidrug antibody level testing allows a more personalised management of patients and improves patient outcomes. This article reviews the data for the use of anti-TNF monitoring and presents a 'how to' guide for clinicians.
| S-EPMC5369465 | biostudies-other
Project description:Inflammatory bowel diseases (IBD) are chronic disorders of the gastrointestinal tract that have been linked to microbiome dysbiosis and immune system dysregulation. We investigated the longitudinal effect of anti-TNF therapy on gut microbiota composition and specific immune response to commensals in IBD patients. The study included 52 patients tracked over 38 weeks of therapy and 37 healthy controls (HC). To characterize the diversity and composition of the gut microbiota, we used amplicon sequencing of the V3V4 region of 16S rRNA for the bacterial community and of the ITS1 region for the fungal community. We measured total antibody levels as well as specific antibodies against assorted gut commensals by ELISA. We found diversity differences between HC, Crohn's disease, and ulcerative colitis patients. The bacterial community of patients with IBD was more similar to HC at the study endpoint, suggesting a beneficial shift in the microbiome in response to treatment. We identified factors such as disease severity, localization, and surgical intervention that significantly contribute to the observed changes in the gut bacteriome. Furthermore, we revealed increased IgM levels against specific gut commensals after anti-TNF treatment. In summary, this study, with its longitudinal design, brings insights into the course of anti-TNF therapy in patients with IBD and correlates the bacterial diversity with disease severity in patients with ulcerative colitis (UC).
| S-EPMC8617723 | biostudies-literature