Statin induced changes in gene expression in EBV-transformed and native B-cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE51444 | GEO | 2013/11/12
SECONDARY ACCESSION(S): PRJNA223179
REPOSITORIES: GEO
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Project description:Statin-induced gene expression differences observed in LCLs may be influenced by their transformation, and thus differ from those observed in native B-cells. To assess this possibility, we prepared LCLs and purified B-cells from the same donors, and compared mRNA profiles after 24hr incubation with simvastatin (2M-BM-5M) or sham buffer. We prepared LCLs and purified B-cells from the same donors, and compared mRNA profiles after 24hr incubation with simvastatin (2M-BM-5M) or sham buffer. Genes involved in cholesterol metabolism were similarly regulated between the two cell types under both the statin and sham treated conditions, and the statin-induced changes were significantly correlated.
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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:We performed a genome-wide association study in pooled DNA samples from patients with severe statin myopathy and persistent symptoms post-therapy versus pooled DNAs from an age-adjusted statin-tolerant group. Affymetrix 100K SNP arrays were used according to the manufacturers instructions with two pools of 19 and 20 statin myopathy patients and two pools of 20 statin-tolerant controls.
2010-07-09 | E-GEOD-17574 | biostudies-arrayexpress
Project description:Statins, the 3-hydroxy-3-methyl-glutaryl (HMG)-CoA reductase inhibitors, are widely prescribed for treatment of hypercholesterolemia. Although statins are generally well tolerated, up to ten percent of patients taking statins experience muscle related adverse events. Myalgia, defined as muscle pain without elevated creatinine phosphokinase (CPK) levels, is the most frequent reason for discontinuation of statin therapy. The mechanisms underlying statin-associated myalgia are not clearly understood. To elucidate changes in gene expression associated with statin-induced myalgia, we compared profiles of gene expression in the biopsied skeletal muscle from statin-intolerant patients undergoing statin re-challenge versus those of statin-tolerant controls. A robust separation of statin-intolerant and statin-tolerant cohorts was revealed by Principal Component Analysis of differentially expressed genes (DEGs). To identify putative gene expression and metabolic pathways that may be perturbed in skeletal muscles of statin intolerant patients, we subjected DEGs to Ingenuity Pathways (IPA) and DAVID (Database for Annotation, Visualization and Integrated Discovery) analyses. The most prominent pathways altered by statins included cellular stress, apoptosis, senescence and DNA repair (TP53, BARD1, Mre11 and RAD51); activation of pro-inflammatory immune response (CXCL12, CST5, POU2F1); protein catabolism, cholesterol biosynthesis, protein prenylation and RAS-GTPase activation (FDFT1, LSS, TP53, UBD, ATF2, H-ras). Based on these data we tentatively conclude that persistent myalgia in response to statins may emanate from cellular stress underpinned by mechanisms of post-inflammatory repair and regeneration. We also posit that this subset of individuals are genetically predisposed to eliciting altered statin metabolism and/or increased end-organ susceptibility that lead to a range of statin-induced myopathies. This mechanistic scenario further bolstered by the discovery that a number of single nucleotide polymorphisms (e.g., SLCO1B1, SLCO2B1 and RYR2) associated with statin myopathy were observed with increased frequency among statin-intolerant study subjects.
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Project description:We performed a genome-wide association study in pooled DNA samples from patients with severe statin myopathy and persistent symptoms post-therapy versus pooled DNAs from an age-adjusted statin-tolerant group.
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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/
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Project description:Global gene expression profiling was performed on paired tumor biopsies collected before and after 2 weeks of statin treatment with the aim of detecting statin induced changes on tumoral gene expression. In this phase II clinical study using the “window-of-opportunity” design, in which the treatment-free window between a cancer diagnosis and surgical tumor resection is used to study the biological effects of a certain drug, atorvastatin, a lipophilic statin, was prescribed to patients with primary breast cancer for two weeks pre-operatively. Tumor samples subjected to whole genome transcriptional profiling were collected before patients started treatment and after completing treatment.
2015-06-23 | E-GEOD-63427 | biostudies-arrayexpress
Project description:Global gene expression profiling was performed on [1] paired tumor biopsies collected before and after 2 weeks of statin treatment [2] a collection of breast cancer cells lines following 48hrs of atorvastatin treatment with the aim of detecting statin induced transcriptional changes in breast cancer cells in-vitro.
2015-06-23 | GSE63427 | GEO
Project description:Statin-induced myopathy is a common side-effect but its mechanisms in human skeletal muscle have never been explained satisfyingly. We exposed 25 different primary human muscle cell lines to either a lipophilic or a hydrophilic statin, quantified cholesterol, mevalonate, proliferation, differentiation, and performed a comprehensive transcriptome and proteome analysis. We found reduced mevalonic acid (MVA) and cholesterol levels demonstrating incorporation of statins into the cells. Statins also significantly impaired proliferation and differentiation. Using an integrated pathway analysis approach with transcriptome and proteome data from statin-treated human primary myotubes, we modelled a novel statin-induced metabolism network for human muscle cells. This analysis confirmed the effect of statins on cholesterol biosynthesis but also uncovered alterations of acetyl CoA-dependent lipid and fatty acid metabolism
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