1 strategy for identifying novel atherosclerosis-related genes and pathways is through a combination of studies using mouse models and human populations. Using this approach, we recently identified 5-lipoxygenase (5-LO), the rate-limiting enzyme in leukotriene (LT) biosynthesis, as a gene with dramatic effects on atherosclerosis susceptibility in mice and humans. The role of LT metabolism in the development of other allergic inflammatory diseases, most notably asthma, is already well known. This proposal, however, will address several fundamental questions that remain to be answered regarding the role of this pathway in coronary artery disease (CAD).
The first aim will determine whether polymorphisms in the major genes of the 5-LO/LT pathway are associated with atherosclerosis using a large cohort of approximately 5,000 individuals on whom the diagnosis of CAD has been definitively assessed by angiography. This will not only confirm the initial observations with 5-LO, but will also determine whether genetic variation in other LT biosynthesis genes are also important for atherogenesis.
The second aim will biochemically characterize the genes and polymorphisms that statistical associations in the first aim have been observed with. To complement these 2 approaches, the third aim focuses on creating additional knock out mouse models for other pathway genes. These mice will allow the genetic dissection of the pathway and the testing of specific hypotheses regarding the patho-physiological mechanism by which LTs increase atherosclerosis. 1 of the long term goals of this project are to develop genetic diagnostic tests that could be used to help identify persons at an increased risk for CAD, much in the same way that traditional risk factors, such as elevated LDL or blood pressure, are presently being used. If the 5-LO/LT pathway proves to be important for CAD, 1 of the most promising benefits could be the application of already existing drugs currently used for asthma to the management of CAD, which could lead to newer and more effective therapies.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL079353-04
Application #
7452453
Study Section
Special Emphasis Panel (ZRG1-CICS (01))
Program Officer
Srinivas, Pothur R
Project Start
2005-08-15
Project End
2010-06-30
Budget Start
2008-07-01
Budget End
2009-06-30
Support Year
4
Fiscal Year
2008
Total Cost
$494,831
Indirect Cost
Name
University of Southern California
Department
Public Health & Prev Medicine
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
O'Sullivan, Aifric; Armstrong, Patrice; Schuster, Gertrud U et al. (2014) Habitual diets rich in dark-green vegetables are associated with an increased response to ?-3 fatty acid supplementation in Americans of African ancestry. J Nutr 144:123-31
Goran, Michael I; Ventura, Emily E (2012) Genetic predisposition and increasing dietary fructose exposure: the perfect storm for fatty liver disease in Hispanics in the U.S. Dig Liver Dis 44:711-3
Hartiala, Jaana; Gilliam, Elizabeth; Vikman, Susanna et al. (2012) Association of PLA2G4A with myocardial infarction is modulated by dietary PUFAs. Am J Clin Nutr 95:959-65
Armstrong, Patrice; Kelley, Darshan S; Newman, John W et al. (2012) Arachidonate 5-lipoxygenase gene variants affect response to fish oil supplementation by healthy African Americans. J Nutr 142:1417-28
Vasunilashorn, Sarinnapha; Finch, Caleb E; Crimmins, Eileen M et al. (2011) Inflammatory gene variants in the Tsimane, an indigenous Bolivian population with a high infectious load. Biodemography Soc Biol 57:33-52
Stephensen, Charles B; Armstrong, Patrice; Newman, John W et al. (2011) ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation. J Lipid Res 52:991-1003
Hartiala, Jaana; Li, Dalin; Conti, David V et al. (2011) Genetic contribution of the leukotriene pathway to coronary artery disease. Hum Genet 129:617-27
Bennett, Brian J; Farber, Charles R; Orozco, Luz et al. (2010) A high-resolution association mapping panel for the dissection of complex traits in mice. Genome Res 20:281-90
Goran, Michael I; Walker, Ryan; Le, Kim-Anne et al. (2010) Effects of PNPLA3 on liver fat and metabolic profile in Hispanic children and adolescents. Diabetes 59:3127-30
Davis, Jaimie N; LĂȘ, Kim-Anne; Walker, Ryan W et al. (2010) Increased hepatic fat in overweight Hispanic youth influenced by interaction between genetic variation in PNPLA3 and high dietary carbohydrate and sugar consumption. Am J Clin Nutr 92:1522-7

Showing the most recent 10 out of 24 publications