Discovering in vivo cytokine eQTL interactions from a lupus clinical trial
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ABSTRACT:
PROVIDER: PRJNA476781 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7367610_1.fastq.gz | Fastqsanger.gz | |||
| SRR7367610_2.fastq.gz | Fastqsanger.gz | |||
| SRR7367620_1.fastq.gz | Fastqsanger.gz | |||
| SRR7367620_2.fastq.gz | Fastqsanger.gz | |||
| SRR7367630_1.fastq.gz | Fastqsanger.gz |
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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:<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 measure interferon (IFN) status, anti-IL-6 drug exposure, and whole blood genome-wide gene expression at three time points. We show that repeat transcriptomic measurements increases the number of cis eQTLs identified compared to using a single time point. We observe a statistically significant enrichment of in vivo eQTL interactions with IFN status and anti-IL-6 drug exposure and find many novel interactions that have not been previously described. Finally, we find transcription factor binding motifs interrupted by eQTL interaction SNPs, which point 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. CONCLUSIONS:This study highlights the potential to exploit clinical trial data to discover in vivo eQTL interactions with therapeutically relevant environmental variables.
| S-EPMC6195724 | biostudies-literature
Project description:eQTL Interactions in Lupus Patients
| PRJNA493878 | ENA
Project description:eQTL Interactions in Lupus Patients
| PRJNA493879 | ENA
Project description:Statins reduce cardiovascular disease risk by lowering plasma low density lipoprotein (LDL)-cholesterol. To identify novel pathways that modulate statin response, we assessed the influence of simvastatin exposure on expression quantitative trait locus (eQTL) associations across the genome in 480 lymphoblastoid cell lines (LCLs). Cell lines were derived blood samples collected ant entry visit from participants in the Cholesterol and Pharmacogenomics (CAP) trial, who underwent a 6 week 40mg/day simvastatin trial. We identified 4590 cis-eQTLS that were independent of treatment status (FDR=1%) and six cis-eQTLS for which there was evidence of an interaction with treatment (FDR=20%). Genotypes and Phenotypes derived from these indivudals are available through dbGaP (Accession Number). eQTL results are available at: http://eqtl.uchicago.edu/cgi=bin/gbrowse/eqtl/
2012-07-01 | GSE36868 | GEO
Project description:Statins reduce cardiovascular disease risk by lowering plasma low density lipoprotein (LDL)-cholesterol. To identify novel pathways that modulate statin response, we assessed the influence of simvastatin exposure on expression quantitative trait locus (eQTL) associations across the genome in 480 lymphoblastoid cell lines (LCLs). Cell lines were derived blood samples collected ant entry visit from participants in the Cholesterol and Pharmacogenomics (CAP) trial, who underwent a 6 week 40mg/day simvastatin trial. We identified 4590 cis-eQTLS that were independent of treatment status (FDR=1%) and six cis-eQTLS for which there was evidence of an interaction with treatment (FDR=20%). Genotypes and Phenotypes derived from these indivudals are available through dbGaP (Accession Number). eQTL results are available at: http://eqtl.uchicago.edu/cgi=bin/gbrowse/eqtl/ Dataset consists of 960 expression beadarrays (Illumina HumanRef-8v3) representing paired samples derived from 24-hour exposures of 480 lymphoblastoid cell lines (LCLs) to 2 micromolar simvastatin acid or control buffer.
2012-06-30 | E-GEOD-36868 | biostudies-arrayexpress
Project description:Mapping of expression quantitative trait loci (eQTL) is a powerful means for elucidating the genetic architecture of gene regulation. Yet, eQTL mapping has not been applied towards investigating the regulation architecture of genes involved in the process of population divergence, ultimately leading to speciation events. Here, we conducted an eQTL mapping experiment to compare the genetic architecture of transcript regulation in adaptive traits differentiating the recently evolved limnetic (dwarf) and benthic (normal) species pairs of lake whitefish. The eQTL were mapped in three data sets derived from a F1 hybrid-dwarf backcrossed family: the entire set of 66 genotyped individuals, and the two sexes treated separately. We identified strikingly more eQTL in the female dataset (174), compared to both male (54) and combined (33) data sets. The majority of these genes were not differentially expressed between male and female progeny of the backcross family, thus providing evidence for a strong pleiotropic sex-linked effect in transcriptomic regulation. The subtelomeric region of a linkage group segregating in females encompassed more than 50% of all eQTL, which exhibited the most pronounced additive effects. We also conducted a direct comparison of transcriptomic profiles between pure dwarf and normal progeny reared in controlled conditions. We detected 34 differentially expressed transcripts associated with eQTL segregating only in sex-specific data-sets, and mostly belonging to functional groups that differentiate dwarf and normal whitefish in natural populations. Therefore, these eQTL are not related to inter-individual variation, but instead to the adaptive and historical genetic divergence between dwarf and normal whitefish. This study exemplifies how the integration of genetic and transcriptomic data offers a strong means for dissecting the functional genomic response to selection by separating mapping family specific effects from genetic factors under selection, potentially involved in the phenotypic divergence of natural populations. Keywords: eQTL mapping
2008-09-01 | GSE11378 | GEO
Project description:Objective: To evaluate the efficacy and safety of the immunotherapeutic vaccine interferon-α kinoid (IFN-K) in a 36-week (W) phase IIb, randomised, double-blind, placebo (PBO)-controlled trial in adults with active systemic lupus erythematosus (SLE) despite standard of care. Methods: Patients with SLE (185) with moderate to severe disease activity and positive interferon (IFN) gene signature were randomised to receive IFN-K or PBO intramuscular injections (days 0, 7 and 28 and W12 and W24). Coprimary endpoints at W36 were neutralisation of IFN gene signature and the BILAG-Based Composite Lupus Assessment (BICLA) modified by mandatory corticosteroid (CS) tapering. Results: IFN-K induced neutralising anti-IFN-α2b serum antibodies in 91% of treated patients and reduce the IFN gene signature (p<0.0001). Modified BICLA responses at W36 did not statistically differ between IFN-K (41%) and PBO (34%). Trends on Systemic Lupus Erythematosus Responder Index-4, including steroid tapering at W36, favoured the IFN- K and became significant (p<0.05) in analyses restricted to patients who developed neutralising anti-IFN-α2b antibodies. Attainment of lupus low disease activity state (LLDAS) at W36 discriminated the two groups in favour of IFN-K (53% vs. 30%, p=0.0022). A significant CS sparing effect of IFN-K was observed from W28 onwards, with a 24% prednisone daily dose reduction at W36 in IFN-K compared with PBO (p=0.0097). The safety profile of IFN-K was acceptable. Conclusions: IFN-K induced neutralising anti-IFN-α2b antibodies and significantly reduced the IFN gene signature with an acceptable safety profile. Although the clinical coprimary endpoint was not met, relevant secondary endpoints were achieved in the IFN-K group, including attainment of LLDAS and steroid tapering. Trial registration number NCT02665364.
2021-10-08 | GSE185047 | GEO