EQTL Interactions in Lupus Patients
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PROVIDER: PRJNA493878 | ENA |
REPOSITORIES: ENA
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Project description:eQTL Interactions in Lupus Patients
| PRJNA493879 | ENA
Project description:<p>The purpose of this study is to discover in vivo cytokine expression quantitative trait locus (eQTL) interactions from a cohort of patients with systemic lupus erythematosus. 157 lupus patients were enrolled in a clinical trial to test the efficacy and safety of an anti-IL-6 monoclonal antibody. At three time points, we measured interferon (IFN) status, anti-IL-6 drug exposure and genome-wide gen expression. We identified 4,818 cis-eQTLs and then observed a statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 exposure.</p>
| phs001702 | dbGaP
Project description:Background: Cytokines are critical to human disease and are attractive therapeutic targets given their widespread influence on gene regulation and transcription. Defining the downstream regulatory mechanisms influenced by cytokines is central to defining drug and disease mechanisms. One promising strategy is to use interactions between expression quantitative trait loci (eQTLs) and cytokine levels to define target genes and mechanisms. Results: In a clinical trial for anti-IL-6 in patients with systemic lupus erythematosus we measured interferon (IFN) status, anti-IL-6 drug exposure and whole blood genome-wide gene expression at three time points (379 samples from 157 individuals). First, we show that repeat transcriptomic measurements increases the number of cis eQTLs identified compared to using a single time point by 64%. Then, after identifying 4,818 cis-eQTLs, we observed a statistically significant enrichment of in vivo eQTL interactions with IFN status (p<0.001 by permutation) and anti-IL-6 drug exposure (p<0.001). We observed 210 and 72 interactions for IFN and anti-IL-6 respectively (FDR<20%). Anti-IL-6 interactions have not yet been described while 99 of the IFN interactions are novel. Finally, we found transcription factor binding motifs interrupted by eQTL interaction SNPs, pointing to key regulatory mediators of these environmental stimuli and therefore potential therapeutic targets for autoimmune diseases. In particular, genes with IFN interactions are enriched for ISRE binding site motifs, while those with anti-IL-6 interactions are enriched for IRF4 motifs. Conclusion: This study highlights the potential to exploit clinical trial data to discover in vivo eQTL interactions with therapeutically relevant environmental variables.
2018-09-24 | GSE116006 | GEO
Project description:Discovering in vivo cytokine eQTL interactions from a lupus clinical trial
| PRJNA476781 | ENA
Project description:Background: Cases where genotype-phenotype relationships depend on environmental factors have been quantified for many complex diseases. Such genotype-environment interactions (GEI or GxE) may also affect expression Quantitative Trait Loci (eQTL) present in tissues critical for the manifestation of disease. To assess this hypothesis, we performed an analysis of eQTL-GEI resulting from an individual's smoking environment in the lung small airway epithelium (SAE). While the SAE is challenging to sample, this is the cell population that shows the first signs of smoking related stress and gene expression in the SAE appears to play a role in mediating smoking effects on lung disease. Results: We used expression microarrays to assay the SAE transcriptome for a small sample of African-American individuals and we analyzed SNPs genotyped genome-wide to identify GEI affecting eQTL. While a genome-wide trans- analysis identified few instances of GEI after a multiple test correction, an analysis of cis-genotypes identified a small but significant number of GEI affecting lung SAE gene expression. We determined that significant cases of eQTL-GEI were not driven by outliers and we were also able to find corroborative evidence for a few of these eQTL-GEI in a small, independent sample of individuals of European ancestry. Conclusion: Given that the power of GEI tests is low compared to tests of genotype association and that the total sample size of our study was small, including only 61 African American individuals in our focal population, the identification of significant GEI in our study implies that there may be considerable genotype-specific effects on eQTL due to smoking environment. We discuss individual cases of GEI of interest for lung disease, such as SDC1 and ZAK, as well as the broader implications of our results for the analysis of eQTL and for genome-wide association analysis of complex diseases.
2024-06-05 | GSE23087 | GEO
Project description:GeneSet variation analysis was performed on microarrays to study the transcriptome of microdissected renal biopsies from lupus nephritis patients.
2023-01-01 | E-MTAB-12257 | biostudies-arrayexpress
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: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:Neutrophils are understudied in lupus. We performed RNA-sequencing of neutrophils from patients with lupus and healthy controls.
2024-06-05 | GSE261866 | 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