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Sökning: WFRF:(Foroughi Asl Hassan)

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  • Bjorkegren, Johan L. M., et al. (författare)
  • Plasma cholesterol-induced lesion networks activated before regression of early, mature, and advanced atherosclerosis.
  • 2014
  • Ingår i: PLoS Genetics. - Public Library of Science. - 1553-7404. ; 10:2
  • Tidskriftsartikel (refereegranskat)abstract
    • Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr(-/-)Apob (100/100) Mttp (flox/flox)Mx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions.
  • Foroughi Asl, Hassan, 1985- (författare)
  • eQTL mapping and inherited risk enrichment analysis : a systems biology approach for coronary artery disease
  • 2016
  • Doktorsavhandling (övrigt vetenskapligt)abstract
    • Despite extensive research during the last decades, coronary artery disease (CAD) remains the number one cause of death, responsible for near 50% of global mortal- ity. A main reason for this is that CAD has a complex inheritance and etiology that unlike rare single gene disorders cannot fully be understood from studies of of genes one-by-one.In parallel, studies that simultaneously assess multiple, function- ally associated genes are warranted. For this reason we undertook the Stockholm Atherosclerosis Gene Expression (STAGE) study that besides careful clinical charac- terization and genome-wide DNA genotyping also assessed the global gene expression profiles from seven CAD-relevant vascular and metabolic tissues. In paper I, we used STAGE to develop a bioinformatics tool for efficient eQTL mapping called kruX based on Kruskal-Wallis statistics test. kruX excels in de- tecting a higher proportion of nonlinear expression quantitative expression traits loci (eQTLs) compared to other established methods. This tool was developed for Python, MATLAB, and R and is available online. In paper II, we applied kruX to detect eQTLs across the seven tissues in STAGE and assessed their tissue speci- ficity. A tool for analyzing inherited risk enrichment was also developed assessing CAD association (i.e., risk enrichment) of STAGE eQTLs according to genome-wide association studies (GWAS) of CAD. We found that eQTLs active across multiple vascular and metabolic tissues are more enriched in inherited risk for CAD than tissue-specific eQTLs. In paper III, we integrate the analysis of STAGE data with data from GWAS of CAD to identify 30 regulatory-gene networks causal for CAD. In paper IV, we again used kruX to investigate STAGE eQTLs for three established candidate genes in CAD and atherosclerosis (ALOX5, ALOX5AP, and LTA4H). In addition, we used the Athero-Express dataset of genotype and atherosclerotic carotid plaque characteristics to further elucidate the role of these genes in atherosclerosis development. In sum, in this thesis report we show that by integrating GWAS with genet- ics of gene expression studies like STAGE, we can advance our understanding from the perspective of multiple genes and gene variants acting in conjunction to cause CAD in the form of regulatory gene networks. This is done through developing new bioinformatics tools and applying them to disease-specific, genetics of global gene expression studies like STAGE. These tools are necessary to go beyond our current limited single-gene understanding of complex traits, like CAD.
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