LP-A PHENOTYPE ATHEROSCLEROSIS

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).