Atherosclerotic coronary disease is the most common cause of mortality in the United States. Mouse models of atherosclerosis have been useful for studying the pathogenesis of atherosclerosis and for the identification of atherosclerosis modifier genes by testing candidate genes through their under or over expression. Additionally, unbiased genetic methods have been used to map the loci of mouse genes that alter atherosclerosis susceptibility;and, the successful identification of a couple of these genes has now been reported. By the use of a strain intercross, we identified the Ath24 and Ath26 loci, which contain genes modifying atherosclerosis susceptibility in female and male mice, respectively. Through the use of gene expression profiling in macrophages derived from the strain intercross cohort, we found genetic loci that are associated with the levels of specific transcripts;and, we identified the genes whose expression was best correlated with atherosclerosis. Remarkably, the best correlated gene in each sex mapped to the corresponding Ath locus for that sex. We propose to confirm the identity of the Ath24 and Ath26 genes, and perform studies to gain insight into their mechanism of action. We also propose to see if genetic variation in the human orthologs of these genes is associated with coronary artery disease (CAD). We present preliminary data that human genetic variation in the top Ath24 and Ath26 gene candidates are in fact associated with CAD.

Public Health Relevance

Atherosclerotic coronary disease (CAD) is the most common cause of mortality in the United States. The proposed studies may identify human genes and pathways not previously recognized to play a role in atherosclerosis. These may lead to diagnostic tools, novel drug targets, and therapies to prevent or treat CAD. Thus, the proposed studies address a significant health concern and offer hope for new modes of risk assessment and prevention.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed AK
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
United States
Zip Code
Hai, Qimin; Ritchey, Brian; Robinet, Peggy et al. (2018) Quantitative Trait Locus Mapping of Macrophage Cholesterol Metabolism and CRISPR/Cas9 Editing Implicate an ACAT1 Truncation as a Causal Modifier Variant. Arterioscler Thromb Vasc Biol 38:83-91
Smith, Jonathan D (2014) New role for histone deacetylase 9 in atherosclerosis and inflammation. Arterioscler Thromb Vasc Biol 34:1798-9
Koeth, Robert A; Levison, Bruce S; Culley, Miranda K et al. (2014) ?-Butyrobetaine is a proatherogenic intermediate in gut microbial metabolism of L-carnitine to TMAO. Cell Metab 20:799-812
Basu, Abhijit; Poddar, Darshana; Robinet, Peggy et al. (2014) Ribosomal protein L13a deficiency in macrophages promotes atherosclerosis by limiting translation control-dependent retardation of inflammation. Arterioscler Thromb Vasc Biol 34:533-42
Teng, Bunyen; Smith, Jonathan D; Rosenfeld, Michael E et al. (2014) A? adenosine receptor deficiency or inhibition reduces atherosclerotic lesions in apolipoprotein E deficient mice. Cardiovasc Res 102:157-65
Robinet, Peggy; Ritchey, Brian; Smith, Jonathan D (2013) Physiological difference in autophagic flux in macrophages from 2 mouse strains regulates cholesterol ester metabolism. Arterioscler Thromb Vasc Biol 33:903-10
Hsu, Jeffrey; Smith, Jonathan D (2013) Genetic-genomic replication to identify candidate mouse atherosclerosis modifier genes. J Am Heart Assoc 2:e005421
Berisha, Stela Z; Hsu, Jeffrey; Robinet, Peggy et al. (2013) Transcriptome analysis of genes regulated by cholesterol loading in two strains of mouse macrophages associates lysosome pathway and ER stress response with atherosclerosis susceptibility. PLoS One 8:e65003
Koeth, Robert A; Wang, Zeneng; Levison, Bruce S et al. (2013) Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 19:576-85
Ding, Liang; Biswas, Sudipta; Morton, Richard E et al. (2012) Akt3 deficiency in macrophages promotes foam cell formation and atherosclerosis in mice. Cell Metab 15:861-72

Showing the most recent 10 out of 15 publications