Dataset Information

Aorta Expression Profiling In HMDP (Atherosclerosis F1 study)

ABSTRACT: Identify genes in the aorta whose expression is under genetic regulation in the Hybrid Mouse Diversity Panel (HMDP). The HMDP comprises classical inbred and recombinant inbred wild type mice. 104 of these strains were bred onto a C57BL/6J background carrying transgenes for both ApoE-Leiden and cholesteryl ester transfer protein (CETP). The RMA values of genes were used for genome wide association as described in Davis et al PLOS Genetics 2015. These data are used to identify candidate genes at loci associated with atherosclerotic lesion size. Overall design: GWAS for expression in aortas of F1 offspring of inbred strains crossed with C57BL/6J carrying ApoE-Leiden and CETP transgenes fed chow diet for 8 weeks followed by Western diet for 16 weeks

INSTRUMENT(S): [HT_MG-430_PM] Affymetrix HT MG-430 PM Array Plate

SUBMITTER: Calvin Pan

PROVIDER: GSE66569 | GEO | 2016-01-25

SECONDARY ACCESSION(S): PRJNA277348

REPOSITORIES: GEO

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Publications

Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains.

Bennett Brian J BJ Davis Richard C RC Civelek Mete M Orozco Luz L Wu Judy J Qi Hannah H Pan Calvin C Packard René R Sevag RR Eskin Eleazar E Yan Mujing M Kirchgessner Todd T Wang Zeneng Z Li Xinmin X Gregory Jill C JC Hazen Stanley L SL Gargalovic Peter S PS Lusis Aldons J AJ

PLoS genetics 20151222 12

Common forms of atherosclerosis involve multiple genetic and environmental factors. While human genome-wide association studies have identified numerous loci contributing to coronary artery disease and its risk factors, these studies are unable to control environmental factors or examine detailed molecular traits in relevant tissues. We now report a study of natural variations contributing to atherosclerosis and related traits in over 100 inbred strains of mice from the Hybrid Mouse Diversity Pa ...[more]

PMID: 26694027

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Project description:Common forms of atherosclerosis involve multiple genetic and environmental factors. While human genome-wide association studies have identified numerous loci contributing to coronary artery disease and its risk factors, these studies are unable to control environmental factors or examine detailed molecular traits in relevant tissues. We now report a study of natural variations contributing to atherosclerosis and related traits in over 100 inbred strains of mice from the Hybrid Mouse Diversity Panel (HMDP). The mice were made hyperlipidemic by transgenic expression of human apolipoprotein E-Leiden (APOE-Leiden) and human cholesteryl ester transfer protein (CETP). The mice were examined for lesion size and morphology as well as plasma lipid, insulin and glucose levels, and blood cell profiles. A subset of mice was studied for plasma levels of metabolites and cytokines. We also measured global transcript levels in aorta and liver. Finally, the uptake of acetylated LDL by macrophages from HMDP mice was quantitatively examined. Loci contributing to the traits were mapped using association analysis, and relationships among traits were examined using correlation and statistical modeling. A number of conclusions emerged. First, relationships among atherosclerosis and the risk factors in mice resemble those found in humans. Second, a number of trait-loci were identified, including some overlapping with previous human and mouse studies. Third, gene expression data enabled enrichment analysis of pathways contributing to atherosclerosis and prioritization of candidate genes at associated loci in both mice and humans. Fourth, the data provided a number of mechanistic inferences; for example, we detected no association between macrophage uptake of acetylated LDL and atherosclerosis. Fifth, broad sense heritability for atherosclerosis was much larger than narrow sense heritability, indicating an important role for gene-by-gene interactions. Sixth, stepwise linear regression showed that the combined variations in plasma metabolites, including LDL/VLDL-cholesterol, trimethylamine N-oxide (TMAO), arginine, glucose and insulin, account for approximately 30 to 40% of the variation in atherosclerotic lesion area. Overall, our data provide a rich resource for studies of complex interactions underlying atherosclerosis.

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