The over-all goal of this project is to characterize the metabolic pathways for a lipoprotein particle containing a complex between apoA and apoB-100. Lp(a) is a risk factor for the development of atherosclerosis and vascular disease, but its metabolic properties are largely unknown. In the preliminary data the investigators have findings arguing against a major role for LDL as a precursor for Lp(a), but the potential precursor role of VLDL has not been clarified. African-Americans have higher Lp(a) levels than Caucasians, but studies to date have failed to provide any molecular and genetic explanation for this difference. Recently the investigators and others have established that the relationships between Lp(a) levels and apoA isoform size differ in African-Americans and Caucasians; elevated Lp(a) levels are present over a wider spectrum of apo(a) sizes in African-Americans compared to Caucasians. Further, they have shown in their preliminary studies that elevated levels of small-size apo(a) is a risk factor for CHD in both African-American and Caucasian men. In view of the significant role of small-size apo(a) as a risk factor for cardiovascular disease, the current lack of understanding of Lp(a) metabolism seriously hampers possibilities for intervention and prevention. The investigators have established techniques for Lp(a) metabolism and for detailed apo(a) phenotyping and genotyping and have access to key populations. In these studies, building on their extensive experience and strength in the Lp(a) field they propose a thematically-linked group of projects that will be provide integrated information on Lp(a) metabolism. The investigators hypothesize in aim 1 that Lp(a) is primarily formed from directly-synthesized apo(a) and apoB, and that circulating apoB is not a major precursor for Lp(a)-apoB; and in aim 2 that in subjects with small-size apo(a) associated with increased risk for CHD, Lp(a) clearance is faster than in subjects with elevated mid-large size apo(a), and apo(a) production is higher than in subjects with low levels of small-size apo(a). Taken together, the investigators expect that information obtained in this proposal will help understand in vivo Lp(a) metabolism and the metabolic basis for elevated levels of small-size apo(a), an independent risk factor for CHD across ethnicity. In addition, the investigators hope that their results with provide a framework for approaches to influence Lp(a) in clinical settings.
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