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.
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/
Project description:<p>The Cholesterol and Pharmacogenetics Study was a 6-week open label, non-randomized study of 40mg/day simvastatin treatment in 335 African-American and 609 Caucasian (944 total) men and women. Plasma lipids and lipoproteins were measured on two occasions prior to treatment and at 4 and 6 weeks of treatment. The study was designed to test for genetic associations with baseline measurements and changes in response to simvastatin treatment.</p> <p>Whole genome genotyping was performed on 592 Caucasian CAP study participants in two stages. In Stage 1, 304 were genotyped for 314,621 SNPs to tag for common genomic variation. In Stage 2, 290 participants were genotyped, including 280 who were genotyped for 620,901 SNPs. Two samples were excluded due to gender discrepancies.</p> <p>PolyA-selected strand-specific RNA-seq libraries were generated from lymphoblastoid cell lines (LCLs) derived from 104 Caucasian and 53 African American CAP participants. The LCLs were exposed to sham buffer (control) or 2 uM activated simvastatin for 24 hours, producing a total of 314 100/101 bp paired end RNA-seq libraries sequenced on Illumina HiSeq 2000 machines.</p>
Project description:The aim of our study was to assess the impact of simvastatin on the amount of cytosolic lipid droplets (LDs), which are implicated in many biological processes including proliferation, inflammation, carcinogenesis, apoptosis, necrosis or growth arrest. Human pancreatic cancer cells MiaPaCa-2 were treated with simvastatin (6 and 12 _M) for 24 hours. Changes in expression of genes related to lipid metabolism in the simvastatin-treated cells were examined by DNA microarray analysis. The treatment of the cells with simvastatin increased their intracellular content of LDs, partially due to the uptake of cholesterol and triacylglycerides from medium; but in particular, due to enhanced synthesis of triacylglycerides as proved by detection of significant overexpression of genes related to de novo synthesis of triacylglycerides and phospholipids. Further, simvastatin markedly influenced expression of genes directly affecting cell proliferation and signaling.
Project description:Statins protect against the development of atherosclerosis via cholesterol-dependent and –independent mechanisms. Understanding the molecular mechanisms mediating simvastatin induced atheroprotective effects is critical for designing anti-atherosclerotic agents. Here, we showed that simvastatin decreases the expression of the Polycomb methyltransferase EZH2 in endothelial cells. To better understand the influence of the simvastatin-induced EZH2 downregulation on endothelial transcriptome, we performed RNA-sequencing study to evaluate differential gene expression after overexpression of EZH2 in the presence of simvastatin treatment. We found simvastatin treatment altered a subset of genes that can be rescued with EZH2 overexpression. Therefore, simvastatin treated endothelial cells display an atheroprotective phenotype by downregulating EZH2.
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.