GENETIC DETERMINANTS OF PLASMA LP(A) CONCENTRATION

描述：中国人血浆脂蛋白(A)[Lp(A)]水平高出2-3倍 非洲人后裔比高加索人多。血浆中的差异 非裔美国人的Lp(A)水平主要是由于序列 与载脂蛋白(A)基因相关的变异，但导致黑人的机制 与其他人群相比，血浆Lp(A)水平升高并不是 为人所知。这项建议的目的是阐明遗传和代谢 高脂血症患者血浆脂蛋白(A)水平升高的机制 非洲裔美国人和非洲黑人(统称为黑人) 与高加索人相比。首先，血浆载脂蛋白(A)亚型的水平将是 比较了一组独特的跨种族家庭的父母和后代 确定血浆Lp(A)水平的差异是否由序列所致 载脂蛋白(A)基因的变异或其他基因的影响。接下来， 将比较黑人和高加索人Lp(A)的代谢，以确定是否 黑人较高的血浆Lp(A)水平是由于 Lp(A)合成减少或分解代谢速度降低。基于 这些研究的结果，我们将在分子水平上检测 Lp(A)合成或分解代谢途径(S)。我们认为，较高的等离子体 黑人的Lp(A)水平是由于分子机制的不同所致 负责载脂蛋白(A)的合成和转运出肝细胞。这 假说将通过检测重组apo(A)的分泌来检验。 培养的黑人和高加索人成纤维细胞的不同大小的异构体。 或者，由于差异，黑人的Lp(A)水平可能更高 以将Lp(A)从循环中移除的方式。因为很少是 已知Lp(A)的分解代谢途径，我们首先将研究两个 推测的Lp(A)受体--极低密度脂蛋白受体和低密度脂蛋白受体相关 使用表达人Lp(A)的转基因小鼠的蛋白质。如果有任何一个 受体参与从血浆中清除Lp(A)，ITS序列 在人类中将被筛查和任何新发现的关系 Lp(A)的序列变异和血浆水平将在家系和 人口。 这些研究将提供对遗传和代谢的更好的理解。 导致黑人血浆Lp(A)水平升高的机制，可能 为这一矛盾的发现提供了新的见解，即黑人没有 尽管有更高的血浆水平，但冠状动脉粥样硬化的发生率更高 Lp(A)水平。

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).