GENETIC DETERMINANTS OF PLASMA LP(A) CONCENTRATION

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DESCRIPTION: Plasma levels of lipoprotein(a) [Lp(a)] are 2-3 times higher in individuals of African descent than in Caucasians. Differences in the plasma levels of Lp(a) among African-Americans are due predominantly to sequence variations linked to the apo(a) gene, but the mechanism responsible for Blacks having elevated plasma levels of Lp(a) relative to other populations is not known. The goal of this proposal is to elucidate the genetic and metabolic mechanisms responsible for the markedly higher plasma levels of Lp(a) in African-Americans and Black Africans (collectively referred to as Blacks) compared to Caucasians. First, the levels of plasma apo(a) isoforms will be compared in parents and offspring of a unique cohort of inter-ethnic families to determine if the differences in plasma levels of Lp(a) are due to sequence variants in the apo(a) gene or to the effect of other genes. Next, the metabolism of Lp(a) in Blacks and Caucasians will be compared to determine if the higher plasma levels of Lp(a) in Blacks are due to an increase in the rate of Lp(a) synthesis or to a decrease in its rate of catabolism. Based on the results of these studies, we will examine at a molecular level either the synthetic or catabolic pathway(s) of Lp(a). We propose that the higher plasma levels of Lp(a) in Blacks are due to differences in the molecular machinery responsible for the synthesis and transport of apo(a) out of liver cells. This hypothesis will be tested by examining the secretion of recombinant apo(a) isoforms of various sizes from cultured fibroblasts of Blacks and Caucasians. Alternatively, the levels of Lp(a) may be higher in Blacks due to a difference in the manner in which Lp(a) is removed from the circulation. Since little is known about catabolic pathways of Lp(a), we first will examine the role of two putative Lp(a) receptors - the VLDL receptor and the LDL receptor related protein using genetically altered mice that express human Lp(a). If either receptor is shown to participate in Lp(a) clearance from plasma, its sequences in humans will be screened and the relationship between any newly identified sequence variants and plasma levels of Lp(a) will be examined in families and populations. These studies will provide a better understanding of the genetic and metabolic mechanisms responsible for the higher plasma levels of Lp(a) in Blacks, and may provide new insights into the paradoxical finding that Blacks do not have a greater incidence of coronary atherosclerosis despite having much higher plasma levels of Lp(a).