High levels of Lp(a) (lipoprotein (a)) are related to greater risk of atherosclerosis in humans, although precise details of the relationship are not known. The baboon, a primate model for research on the interaction of lipoproteins and atherosclerosis, possesses Lp (a) that is similar to human Lp (a) in every respect. We have developed techniques for quantitating aspects of Lp(a) phenotype, including total serum concentration, individual isoform levels, and the lipoprotein density. The goals for this proposal are to determine the relationship between Lp(a) phenotype and atherosclerosis in the baboon model, and to develop a better understanding of the genetic and dietary factors that mediate Lp(a) phenotype. These studies are important to the long-term objective of developing therapies in the baboon model that will help reduce the risk of cardiovascular disease due to the presence of Lp(a). This proposal has five Specific Aims: 1) determine the frequency of occurrence of Lp(a) phenotypes in a population of unrelated baboons; 2) test the hypothesis that Lp(a) phenotype is related to extent of arterial atherosclerotic lesions. Lp(a) phenotype in 320 baboons will be evaluated in relation to extent of atherosclerosis assessed following necropsy; 3) test the hypothesis that postprandial forms of Lp(a) are related to extent of atherosclerotic lesions. We will determine the postprandial Lp(a) phenotype (120 baboons) which will be evaluated in relation to extent of atherosclerosis; 4) test the hypothesis that Lp(a) phenotype is responsive to diet. Lp(a) phenotype will be determined and correlated with a consistent change in levels of dietary fat and cholesterol in 100 baboons. Ethanol is reported to decrease human Lp(a) levels, and we will correlate Lp(a) phenotype with changes in amount of dietary ethanol in eight baboons; and 5) test the hypothesis that two major genes control the various aspects of Lp(a) phenotype using samples from members of a pedigreed colony. Understanding dietary and genetic influences on Lp(a) phenotype, and its association with atherosclerosis, will help us plan strategies to reduce the risk of cardiovasular disease due to the presence of Lp(a).
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