title: Genetic Architecture of Atherosclerosis in Mice: A Systems Genetics Analysis of Common Inbred Strains.
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.
authors.affiliation: Departments of Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Bennett
authors.affiliation: Departments of Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Richard C
authors.initials: RC
authors.lastname: Davis
authors.affiliation: Departments of Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Mete
authors.initials: M
authors.lastname: Civelek
authors.affiliation: Departments of Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Luz
authors.initials: L
authors.lastname: Orozco
authors.affiliation: Departments of Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Judy
authors.initials: J
authors.lastname: Wu
authors.affiliation: Departments of Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Hannah
authors.initials: H
authors.lastname: Qi
authors.affiliation: Departments of Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Calvin
authors.initials: C
authors.lastname: Pan
authors.affiliation: Departments of Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: René R Sevag
authors.initials: RR
authors.lastname: Packard
authors.affiliation: Department of Computer Science, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Eleazar
authors.initials: E
authors.lastname: Eskin
authors.affiliation: Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Princeton, New Jersey, United States of America.
authors.forename: Mujing
authors.initials: M
authors.lastname: Yan
authors.affiliation: Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Princeton, New Jersey, United States of America.
authors.forename: Todd
authors.initials: T
authors.lastname: Kirchgessner
authors.affiliation: Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States of America.
authors.forename: Zeneng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States of America.
authors.forename: Xinmin
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States of America.
authors.forename: Jill C
authors.initials: JC
authors.lastname: Gregory
authors.affiliation: Department of Cellular and Molecular Medicine (NC10), Cleveland Clinic Lerner Research Institute, Cleveland, Ohio, United States of America.
authors.forename: Stanley L
authors.initials: SL
authors.lastname: Hazen
authors.affiliation: Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Princeton, New Jersey, United States of America.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Gargalovic
authors.affiliation: Departments of Medicine, Human Genetics, and Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, Los Angeles, California, United States of America.
authors.forename: Aldons J
authors.initials: AJ
authors.lastname: Lusis
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000235:genetics / Q000378:metabolism; D050197:Atherosclerosis / Q000235:genetics* / Q000473:pathology; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics* / Q000378:metabolism; D008078:Cholesterol, LDL / Q000097:blood; D006801:Humans; D007178:Inbreeding; D007328:Insulin / Q000097:blood; D008264:Macrophages / Q000378:metabolism; D008744:Methylamines / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D040641:Quantitative Trait Loci; D059467:Transcriptome
chemical_list: D001057:Apolipoproteins E; C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D008078:Cholesterol, LDL; D007328:Insulin; D008744:Methylamines; C005855:trimethyloxamine