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Abstract
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.
Highlights
Inheritance plays an important role in the pathogenesis of coronary artery disease (CAD), the leading cause of death in the developed world [1,2,3,4]
While recent genetic association studies in human populations have succeeded in identifying genetic loci that contribute to coronary artery disease (CAD) and related phenotypes, these loci explain only a small fraction of the genetic variation in CAD and associated traits
A striking finding was the large fraction of atherosclerosis that was explained by genetic interactions
Summary
Inheritance plays an important role in the pathogenesis of coronary artery disease (CAD), the leading cause of death in the developed world [1,2,3,4]. Recent genome-wide association studies (GWAS), involving hundreds of thousands of individuals have identified numerous loci contributing to CAD traits and to risk factors such as blood lipoprotein levels and blood pressure. Most of the loci identified do not contain known candidates; for example, data from nearly 200,000 people identified 46 genetic loci associated with CAD, but only 17 of these loci contain genes for known risk factors such as lipids and blood pressure [5]. Novel loci contributing to CAD have been successfully dissected using a combination of human and experimental mouse studies [7,8,9]. Such GWAS and follow-up studies do, have some important limitations. For most traits that have been studied, even very large association studies explain a small fraction of the heritability of the traits [9, 10]
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