A longitudinal and transancestral analysis of DNA methylation patterns and disease activity in lupus patients
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ABSTRACT:
PROVIDER: PRJNA678368 | ENA |
REPOSITORIES: ENA
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Project description:Epigenetic dysregulation is implicated in the pathogenesis of lupus. We performed a longitudinal analysis to assess changes in DNA methylation in neutrophils collected from 54 lupus patients over 4 years of follow up and across disease activity levels using 229 patient samples.
2020-12-08 | GSE161476 | GEO
Project description:Epigenetic dysregulation is implicated in the pathogenesis of lupus. We performed a longitudinal analysis to assess changes in DNA methylation in lupus neutrophils over 4 years of follow-up and across disease activity levels using 229 patient samples. We demonstrate that DNA methylation profiles in lupus are partly determined by ancestry-associated genetic variations and are highly stable over time. DNA methylation levels in 2 CpG sites correlated significantly with changes in lupus disease activity. Progressive demethylation in SNX18 was observed with increasing disease activity in African American patients. Importantly, demethylation of a CpG site located within GALNT18 was associated with the development of active lupus nephritis. Differentially methylated genes between African American and European American lupus patients include type I IFN-response genes such as IRF7 and IFI44, and genes related to the NF-κB pathway. TREML4, which plays a vital role in TLR signaling, was hypomethylated in African American patients and demonstrated a strong cis-methylation quantitative trait loci (cis-meQTL) effect among 8855 cis-meQTL associations identified in our study.
| S-EPMC7710270 | biostudies-literature
Project description:Systemic lupus erythematosus (SLE) is a chronic-relapsing autoimmune disease of incompletely understood etiology. Recent evidence strongly supports an epigenetic contribution to the pathogenesis of lupus. To understand the extent and nature of dysregulated DNA methylation in lupus T cells, we performed a genome-wide DNA methylation study in CD4+ T cells from 12 lupus patients and 12 normal healthy controls. Cytosine methylation was quantified in 27,578 CG pairs located within the promoter regions of 14,495 genes. We identified 236 hypomethylated and 105 hypermethylated CG sites in lupus CD4+ T cells compared to normal controls, consistent with a global hypomethylation in lupus T cells. Further analysis identified hypomethylation in genes involved in connective tissue development including CD9, MMP9, and PDGFRA. Hypermethylated genes highlight “response to nutrients” ontology such as folate biosynthesis, suggesting a link between environmental factor and lupus and emphasizing the role of folate in DNA methylation. In addition, the transcription factor RUNX3 was hypermethylated in lupus CD4+ T cells. Protein-protein interaction maps identified a transcription factor, HNF4a, as a regulatory hub affecting a number of differentially methylated genes. Functional annotations such as apoptosis is also overrepresented. Further, our data indicate that the methylation status of certain genes predicts disease activity in lupus patients. This work provides a foundation to begin identifying novel pathogenic pathways in lupus T cells and developing novel epigenetic biomarkers for disease activity in lupus. We employed microarray-based technologies to perform a genome-wide DNA methylation assay and quantify CD4+ T cell DNA methylation levels at 27,578 CG sites spanning 14,495 genes of 11 lupus patients and 12 healthy controls.
2011-06-10 | E-GEOD-27895 | biostudies-arrayexpress
Project description:The highly heterogeneous clinical presentation of lupus is characterized by the unpredictable appearance of flares of disease activity and important organ damage. Attempts to stratify lupus patients have been limited to clinical information, leading to unsuccessful clinical trials and controversial research results. Our aim was to develop and validate a robust method to stratify patients with lupus according to longitudinal disease activity and whole-genome gene expression data in order to establish subgroups of patients who share disease progression mechanisms. We applied a clustering-based approach to stratify SLE patients based on the correlation between disease activity scores and longitudinal gene expression information. Clustering robustness was evaluated by bootstrapping and the clusters were characterized in terms of clinical and functional features.Using two independent sets of patients, one pediatric and another adult, our results show a clear partition into three different disease clusters not influenced by treatment, race or other source of bias. Two of the clusters differentiate into a neutrophil correlated disease group and a lymphocyte correlated disease group, while the third that correlated to a lesser extent with neutrophils, was functionally more heterogeneous. The neutrophil-driven clusters were associated with increased development towards proliferative nephritis. We found three subgroups of patients that show different mechanisms of disease progression and are clinically differentiated. Our results have important implications for treatment options, the design of clinical trials, the etiology of the disease, and the prediction of severe glomerulonephritis.
2018-10-15 | GSE121239 | GEO
Project description:Systemic lupus erythematosus (SLE) is a chronic-relapsing autoimmune disease of incompletely understood etiology. Recent evidence strongly supports an epigenetic contribution to the pathogenesis of lupus. To understand the extent and nature of dysregulated DNA methylation in lupus T cells, we performed a genome-wide DNA methylation study in CD4+ T cells from 12 lupus patients and 12 normal healthy controls. Cytosine methylation was quantified in 27,578 CG pairs located within the promoter regions of 14,495 genes. We identified 236 hypomethylated and 105 hypermethylated CG sites in lupus CD4+ T cells compared to normal controls, consistent with a global hypomethylation in lupus T cells. Further analysis identified hypomethylation in genes involved in connective tissue development including CD9, MMP9, and PDGFRA. Hypermethylated genes highlight “response to nutrients” ontology such as folate biosynthesis, suggesting a link between environmental factor and lupus and emphasizing the role of folate in DNA methylation. In addition, the transcription factor RUNX3 was hypermethylated in lupus CD4+ T cells. Protein-protein interaction maps identified a transcription factor, HNF4a, as a regulatory hub affecting a number of differentially methylated genes. Functional annotations such as apoptosis is also overrepresented. Further, our data indicate that the methylation status of certain genes predicts disease activity in lupus patients. This work provides a foundation to begin identifying novel pathogenic pathways in lupus T cells and developing novel epigenetic biomarkers for disease activity in lupus.
2011-06-10 | GSE27895 | GEO
Project description:To screen specific DNA methylation markers in systemic lupus erythematosus (SLE) patient's blood DNA, whole-blood DNAs from 6 female SLE patients and 6 female controls were analyzed by methylation microarray.
2016-12-27 | GSE57869 | GEO
Project description:Transcriptional modules were used as a basis for the selection of biomarkers and the development of a multivariate transcriptional indicator of disease progression in patients with systemic lupus erythematosus. Experiment Overall Design: The proposed biomarker-selection strategy relies on modules for reducing highly dimensional microarray data sets in a stepwise manner. Starting from the full set of 28 modules, only those for which a set minimum proportion of transcripts are significantly changed between the study groups are selected (e.g., minimum proportion of differentially expressed transcripts at p < 0.05 = 15% overexpressed or underexpressed transcripts; in the example given, 11 SLE modules meet this criterion). This eliminates from the selection pool the modules registering fewer consistent changes that could be attributed to noise. Transcriptional vectors were derived for the entire cohort of 22 untreated pediatric SLE patients with the use of this set of 11 SLE modules. Patient profiles were also generated for an independent set of 31 children with SLE treated with steroids and/or cytotoxic drugs and/or hydroxychloroquine. A nonparametric method for analyzing multivariate ordinal data was used to score the patients. Lupus disease flares can lead to irreversible worsening of the patient's status. We tested the relevance of this multivariate transcriptional score for longitudinal monitoring of the disease activity in a cohort of 20 pediatric SLE patients (two to four time points/patient, intervals between each time point varied from one month to 18 months). Half of the patients had been included in our cross-sectional analysis before they were enrolled in this longitudinal study. Parallel trends were observed between multivariate transcriptional scores and a clinical severity score. The positive association was verified statistically with the use of a linear-regression model. Experiment Overall Design:
2008-10-01 | E-GEOD-11909 | biostudies-arrayexpress
Project description:Methyl-seq data was obtained from total peripheral blood mononuclear cells of two patients with systemic lupus erythematosus who were characterized as having>2 standard deviations more ARID3a-expressing B lymphocytes than healthy controls. Similarly, methyl-seq data was also obtained from two SLE patient samples with normal (low) numbers of ARID3-expressing B lymphocytes. Our previous studies showed that increased ARID3a expression in B lymphocytes was associated increased disease activity. Data were generated on an Illumina Hiseq 2000 with paired-end 100bp reads and quality control metrics were assessed with Picard tools.
2016-08-19 | GSE84965 | GEO
Project description:Methyl-seq data was obtained from total peripheral blood mononuclear cells of two patients with systemic lupus erythematosus who were characterized as having>2 standard deviations more ARID3a-expressing B lymphocytes than healthy controls. Similarly, methyl-seq data was also obtained from two SLE patient samples with normal (low) numbers of ARID3-expressing B lymphocytes. Our previous studies showed that increased ARID3a expression in B lymphocytes was associated increased disease activity. Data were generated on an Illumina Hiseq 2000 with paired-end 100bp reads and quality control metrics were assessed with Picard tools. Methylation profiles of genomic DNA from four SLE patient PBMC samples, two with high numbers of ARID3a expressing B cells (ARID3aH) versus two with normal numbers of ARID3a+ B cells (ARID3aN), were generated on an Illumina Hiseq 2000 with paired-end 100bp reads.
2016-08-19 | E-GEOD-84965 | biostudies-arrayexpress
Project description:Disease progression and therapeutic resistance are hallmarks of advanced stage prostate cancer (PCa), which remains a major cause of cancer-related mortality around the world. Longitudinal studies, coupled with the use of liquid biopsies, offer a potentially new and minimally invasive platform to study the dynamics of tumour progression. Our study aimed to investigate the dynamics of personal methylomic profiles of metastatic PCa (mPCa) patients, during disease progression and therapy administration. 52 plasma samples from 9 patients with mPCa were collected, longitudinally, over 13-21 months. After cell-free DNA (cfDNA) isolation, DNA methylation was profiled using the Infinium MethylationEPIC BeadChip and analysed using the minfi software. The top 5% most variable probes across time, within each individual, were utilised to study dynamic methylation patterns during disease progression and therapeutic response. Statistical testing was carried out to identify and validate ctDNA differentially methylated genes (DMGs). Personal cfDNA global methylation patterns were temporally stable throughout disease course. A proportion of analysed CpG sites presented a dynamic temporal pattern that was consistent with clinical events, such as therapy administration, and were prominently associated with immune response pathways. Study of ctDNA identified >2,000 DMGs with dynamic methylation patterns. We concluded that longitudinal assessment of cfDNA methylation in mPCa patients unveiled dynamic patterns associated with the occurrence of specific clinical events, thus highlighting the potential of using liquid biopsies to study PCa progression.
2021-09-01 | GSE157273 | GEO