Identification and validation of causal genes for atherosclerosis in mice
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
SUBMITTER: Xia Yang
PROVIDER: E-GEOD-18479 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Identification and validation of genes affecting aortic lesions in mice.
Yang Xia X Peterson Larry L Thieringer Rolf R Deignan Joshua L JL Wang Xuping X Zhu Jun J Wang Susanna S Zhong Hua H Stepaniants Serguei S Beaulaurier John J Wang I-Ming IM Rosa Ray R Cumiskey Anne-Marie AM Luo Jane Ming-Juan JM Luo Qi Q Shah Kashmira K Xiao Jianying J Nickle David D Plump Andrew A Schadt Eric E EE Lusis Aldons J AJ Lum Pek Yee PY
The Journal of clinical investigation 20100623 7
Atherosclerosis represents the most significant risk factor for coronary artery disease (CAD), the leading cause of death in developed countries. To better understand the pathogenesis of atherosclerosis, we applied a likeli-hood-based model selection method to infer gene-disease causality relationships for the aortic lesion trait in a segregating mouse population demonstrating a spectrum of susceptibility to developing atherosclerotic lesions. We identified 292 genes that tested causal for aorti ...[more]
Similar Datasets
Project description:Aortic arch profiling of Ldlr-/- huCETP transgenic mice fed a low fat, cholesterol-containing western diet (LFWD, 9% fat, 0.15% cholesterol) starting at 8 weeks of age for 4, 8, 12, and 16 weeks. Ldlr-/- huCETP transgenic mice were fed a low fat, cholesterol-containing western diet (LFWD, 9% fat, 0.15% cholesterol) starting at 8 weeks of age for 4, 8, 12, and 16 weeks (Supplementary Figure 1). At each time point, 10 mice were studied. Mice were euthanized at each time point and the aortic arch of each mouse was immediately collected and flash-frozen in liquid N2. Mice were fasted overnight prior to euthanasia. the aortic arches of 10 mice in the same study group were pooled for profiling, resulting in one pool per study group. Tissues were homogenized and total RNA was extracted. The control RNA pool was composed of equal aliquots of RNA derived from the 4 pools (40 samples) from the LFWD 4-, 8-, 12- and 16-week time points.
2010-06-22 | E-GEOD-18442 | biostudies-arrayexpress
Project description:Aortic arch profiling of Apoe-/- mice fed a high fat diet (HFD, Harlan Teklad 88137, 21% fat, 0.15% cholesterol) starting at 8 weeks of age for 8, 16, and 24 weeks. B6 mice fed HFD for 16 weeks starting at 8 weeks of age were used as controls. Apoe-/- mice were fed a high fat diet (HFD, Harlan Teklad 88137, 21% fat, 0.15% cholesterol) starting at 8 weeks of age for 8, 16, and 24 weeks. B6 mice fed HFD for 16 weeks starting at 8 weeks of age were used as controls. At each time point, 9 mice were studied. Mice were euthanized at each time point and whole aorta (from aortic root to renal bifurcation) of each mouse was immediately collected and flash-frozen in liquid N2. Mice were fasted overnight prior to euthanasia. the aortic arches of three mice in the same study group were pooled, resulting in three pools per study group.
2010-06-22 | E-GEOD-18443 | biostudies-arrayexpress
Project description:Atherosclerosis is the leading underlying cause of death worldwide. We reported a mouse model of atherosclerosis regression that involves transplanting an atherosclerotic aortic arch into a normolipidemic mouse. There, emigration of plaque foam cells occurred in a CCR7 (dendritic cell migration factor) dependent manner. It was obvious, though, that other pathways are likely to be involved in this process. We therefore performed microarrays on laser captured macrophages isolated from the progression and regression environments. This yielded two major findings. Firstly, genes associated with the contractile apparatus (such as actin and myosin) that are responsible for cellular movement were differentially up-regulated under regression conditions with members of the cadherin family (serves in adhesion functions) being significantly down-regulated. Secondly, the most highly up-regulated gene under regression was arginase I, a classical marker of the M2 alternative activated macrophage. Further examination revealed that regression was characterized by macrophages displaying other M2 markers such as CD163, C-lectin receptor, mannose receptor, and Fizz-1. In addition, we applied recently introduced local causal pathway discovery methods to our microarray data that revealed that genes such as vinculin and ApoCII may play a role in the pathophysiology of atherosclerosis regression. Ultimately, the insights gained from the regression model and the different modes of analyses should lead to new therapeutic targets against cardiovascular disease. We performed microarrays on laser captured macrophages isolated from aortic arch from mouse in atherosclerosis progression and regression environments (C57Bl/6, ApoE -/-). Study was performed in two batches, with three treatment groups each: progression, regression and baseline. Profiled in the Merck/Agilent 3.0
2011-09-30 | E-GEOD-24819 | biostudies-arrayexpress
Project description:Lipoprotein lipase (Lpl) was predicted as a causal gene for abdominal using a novel statistical method named LCMS (Schadt et al., 2005, Nature Genetics). In order to validate this prediction, we profiled the liver tissues of lipoprotein lipase heterozygous knockout mice (Lpl+/-) and their littermate wild-type (wt) controls to examine the gene expression signature as well as pathways/networks resulting from the single gene perturbation. 8 Lpl+/- mice and 8 wt controls were profiled. Reference pool included RNA extracted from the liver of 9 wt control mice. Dye-swap was involved in the profiling.
2009-03-07 | E-GEOD-11991 | biostudies-arrayexpress
Project description:Cytosolic malic enzyme (Me1) was predicted as a causal gene for abdominal using a novel statistical method named LCMS (Schadt et al., 2005, Nature Genetics). In order to validate this prediction, we profiled the liver tissues of Me1 knockout mice (Me1-/-) and their littermate wild-type (wt) controls to examine the gene expression signature as well as pathways/networks resulting from the single gene perturbation. 3 Me1-/- mice and 5 wt controls were profiled. Reference pool included RNA extracted from the liver of 5 wt control mice. Dye-swap was involved in the profiling.
2009-03-07 | E-GEOD-11992 | biostudies-arrayexpress
Project description:Transforming growth factor beta receptor 2 (Tgfbr2) was predicted as a causal gene for abdominal using a novel statistical method named LCMS (Schadt et al., 2005, Nature Genetics). In order to validate this prediction, we profiled the liver tissues of Tgfbr2 heterozygous knockout mice (Tgfbr2+/-) and their littermate wild-type (wt) controls to examine the gene expression signature as well as pathways/networks resulting from the single gene perturbation. 6 Tgfbr2+/- mice and 4 wt controls were profiled. Reference pool included RNA extracted from the liver of 6 wt control mice. Dye-swap was involved in the profiling.
2009-03-07 | E-GEOD-11994 | biostudies-arrayexpress
Project description:Complement component 3a receptor 1 (C3ar1) was predicted as a causal gene for abdominal using a novel statistical method named LCMS (Schadt et al., 2005, Nature Genetics). In order to validate this prediction, we profiled the liver tissues of complement component 3a receptor 1 knockout (C3ar1-/-) mice and their littermate wild-type (wt) controls to examine the gene expression signature as well as pathways/networks resulting from the single gene perturbation. 3 C3ar1-/- mice and 4 wt controls were profiled. Reference pool included RNA extracted from the liver of 6 wt control mice. Dye-swap was involved in the profiling.
2009-03-07 | E-GEOD-11995 | biostudies-arrayexpress
Project description:A major task in dissecting the genetics of complex traits is to identify causal genes for disease phenotypes. We previously developed a method to infer causal relationships among genes through the integration of DNA variation, gene transcription, and phenotypic information. Here we validated our method through the characterization of transgenic and knockout mouse models of candidate genes that were predicted to be causal for abdominal obesity. Perturbation of eight out of the nine genes, with Gas7, Me1 and Gpx3 being novel, resulted in significant changes in obesity related traits. Liver expression signatures revealed alterations in common metabolic pathways and networks contributing to abdominal obesity and overlapped with a macrophage-enriched metabolic network module that is highly associated with metabolic traits in mice and humans. Integration of gene expression in the design and analysis of traditional F2 intercross studies allows high confidence prediction of causal genes, and identification of involved pathways and networks. This SuperSeries is composed of the following subset Series: GSE11991: Liver gene expression profiling of lipoprotein lipase heterozygous knockout mice GSE11992: Liver gene expression profiling of cytosolic malic enzyme knockout mice GSE11993: Liver gene expression profiling of zinc finger binding protein 90 (Zfp90) transgenic mice GSE11994: Liver gene expression profiling of transforming growth factor beta receptor 2 heterozygous knockout (Tgfbr2+/-) mice GSE11995: Liver gene expression profiling of complement component 3a receptor 1 knockout (C3ar1-/-) mice GSE11996: Gas7 male transgenic liver expression vs FVB male wildtype control GSE11997: Gpx3 male transgenic liver expression vs B6/DBA male wildtype control GSE11998: Gyk female heterozygous liver expression vs C57Bl/6J female wildtype control GSE11999: Lactb male transgenic liver expression vs FVB male wildtype control Refer to individual Series
2009-03-07 | E-GEOD-12000 | biostudies-arrayexpress
Project description:To identify the genes and pathways that underlie cardiovascular and metabolic phenotypes we performed an integrated analysis of a mouse C57BL/6J x A/J F2 (B6AF2) cross by relating genome-wide gene expression data from adipose, kidney, and liver tissues to physiological endpoints measured in the population. We have identified a large number of trait QTLs including loci driving variation in cardiac function on chromosomes 2 and 6 and a hotspot for adiposity, energy metabolism, and glucose traits on chromosome 8. Integration of adipose gene expression data identified a core set of genes that drive the chromosome 8 adiposity QTL. This chromosome 8 trans eQTL signature contains genes associated with mitochondrial function and oxidative phosphorylation and maps to a subnetwork with conserved function in humans that was previously implicated in human obesity. In addition, human eSNPs corresponding to orthologous genes from the signature show enrichment for association to type II diabetes in the DIAGRAM cohort, supporting the idea that the chromosome 8 locus perturbs a molecular network that in humans senses variations in DNA and in turn affects metabolic disease risk. We functionally validate predictions from this approach by demonstrating metabolic phenotypes in knockout mice for three genes from the trans eQTL signature, Akr1b8, Emr1, and Rgs2. In addition we show that the transcriptional signatures for knockout of two of these genes, Akr1b8 and Rgs2, map to the F2 network modules associated with the chromosome 8 trans eQTL signature and that these modules are in turn very significantly correlated with adiposity in the F2 population. Overall this study demonstrates how integrating gene expression data with QTL analysis in a network-based framework can aid in the elucidation of the molecular drivers of disease that can be translated from mice to humans. An F2 population was derived from a C57BL/6J x A/J mouse cross (B6AF2) and tissues were collected in 360 male and female progeny for microarray analysis. RNA extraction, probe preparation, and array hybridizations were all carried out at the Rosetta Inpharmatics Gene Expression Laboratory (Seattle, WA). Mouse tissues (gonadal adipose, kidney medulla, kidney cortex, hypothalamus) were pulverized prior to homogenization in a solution of GITC/BME (1:50 ratio) using a Covaris S2 cryo-prep (Covaris, Inc, Woburn, MA), followed by addition of a TRIzol water solution (4:1 ratio). 100% Chloroform was added to the TRIzol/GITC lysate (1:5 ratio) to facilitate separation of the organic and aqueous components using the phaselock (Eppendorf) system. The aqueous supernatant was further purified using a Promega SV-96 total RNA kit (Promega, Madison, WI), incorporating a DNase treatment. Total RNA samples were assayed for quality using an Agilent Bioanalyzer (Agilent Technologies, Santa Clara, CA) and for yield using Ribogreen (Ambion, Austin, TX) metrics prior to amplification. All samples, with the exception of kidney medulla, were amplified and labeled using a custom automated version of a 5 µg RT/IVT protocol and hybridizations to custom Agilent microarrays were performed as described [58]. The custom ink-jet microarrays used in this study were manufactured by Agilent Technologies and consisted of 4,732 control probes and 39,558 non-control oligonucleotides derived from mouse Unigene clusters, combined with RefSeq sequences and RIKEN full-length cDNA clones. For each individual animal tissue sample, labeled complementary RNA (cRNA) was hybridized against a pool of labeled cRNAs constructed from equal aliquots of RNA for that specific tissue from at least 200 individuals.
2011-01-13 | E-GEOD-25506 | biostudies-arrayexpress
Project description:To map the genetics of gene expression in metabolically relevant tissues and investigate the diversity of expression SNPs (eSNPs) in multiple tissues from the same individual, we collected four tissues from approximately 1,000 patients undergoing Roux-en-y gastric bypass and clinical traits associated with their weight loss and co-morbidities. We then performed high-throughput genotyping and gene expression profiling and carried out a genome-wide association analyses for more than one hundred thousand gene expression traits representing four metabolically relevant tissues; liver, omental adipose, subcutaneous adipose and stomach. We successfully identified 24,531 eSNPs corresponding to ~10,000 distinct genes. This represents the greatest number of eSNPs identified to our knowledge by any study to date and the first study to identify eSNPs from stomach tissue. We then demonstrate how these eSNPs provide a high quality disease map for each tissue in morbidly obese patients to not only inform genetic associations indentified in this cohort, but in previously published genome wide association studies as well. eSNPs and gene co-expression modules identification in morbidly obese patients represent a great resource that will aid in elucidating the key networks associated with morbid obesity, response to RYGB and disease as a whole. Keywords: Tissue profiling in a human cohort. Liver tissue was collected from patients at the time of RYGB surgery at Massachusetts General Hospital between 2000 and 2007. Samples were collected in RNAlater (Ambion/Applied Biosystems), stored at -80° and shipped to Rosetta Inpharmatics Gene Expression Laboratory Seattle, WA for extraction, amplification, labeling, and microarray processing. Samples processed ranged in size from 100-200mg. Total RNA extracted from liver was converted to fluorescently labeled cRNA that was hybridized to custom 44K DNA oligonucleotide microarrays manufactured by Agilent Technologies as described previously (Hughes et al. 2001; Schadt et al. 2008). Successful gene expression profiling results were collected from 651 liver samples.
2011-04-01 | E-GEOD-24293 | biostudies-arrayexpress