GENETIC DETERMINANTS OF PLASMA LP(A) CONCENTRATION

描述：(摘自摘要)Lp(A)是一种致动脉粥样硬化 一种含有独特糖蛋白载脂蛋白的脂蛋白 [Apo(A)]。载脂蛋白(A)亚型显示出巨大的大小差异 个人。对这种变异性的分子基础的解释是 受技术问题的阻碍，在处理含有 与纤溶酶原共享的多个重复序列和若干 假基因。这位调查员通过使用 脉冲场凝胶电泳法鉴定基因组DNA片段 它包含编码kringle4的大部分外显子，主要重复 载脂蛋白(A)中的序列。这个基因组片段的大小与 不同个体的载脂蛋白(A)的大小，表明 不同的载脂蛋白(A)等位基因具有不同数量的kringle4编码 重复着。 这一发现提供了一个分子句柄来分析 Apo(A)基因，并检测其在测定血浆中的作用 人类Lp(A)水平。调查人员在高加索人中表明 载脂蛋白(A)基因的序列变异是最重要的 血浆脂蛋白(A)水平的决定因素。具体的问题是 研究人员现在要解决的问题是：1)为什么血浆Lp(A)水平 高加索人和非裔美国人之间的差异？其中有多少 变异是由于载脂蛋白(A)基因座的差异吗？3) 载脂蛋白(A)基因座影响血浆水平的结构决定因素 在Lp(A)的致动脉粥样硬化方面？4)最后， 影响低密度脂蛋白代谢调节血浆脂蛋白(A)水平？ 为了回答这些问题，调查员将执行以下操作：1)家庭 研究确定血浆Lp(A)水平是否与 非裔美国人载脂蛋白(A)基因；2)家系分析以确定 低密度脂蛋白受体和载脂蛋白(B)基因突变对血浆的影响 Lp(A)水平；3)部分载脂蛋白(A)等位基因的分子特征 与血浆Lp(A)水平高或低有关； 4)冠状动脉相关载脂蛋白(A)等位基因的分子特征 动脉疾病；最后是组织培养和动物研究 目的是在其真实的基因组环境中表达载脂蛋白(A)基因。 通过了解更多关于载脂蛋白(A)基因结构及其与 血浆Lp(A)水平研究人员将深入了解 脂蛋白(A)在动脉粥样硬化形成中的作用机制。

DESCRIPTION: (adapted from the abstract) Lp(a) is an atherogenic lipoprotein that contains a unique glycoprotein, apolipoprotein [apo(a)]. Apo (a) isoforms exhibit enormous size variation among individuals. Elucidation of the molecular basis of this variability was hampered by technical problems in dealing with a gene containing multiple repeated sequences that are shared with plasminogen and several pseudogenes. The investigator overcame many of these problems by using pulsed-field gel electrophoresis to identify a fragment of genomic DNA that contains most of the exons encoding kringle 4, the major repeated sequence in apo(a). The size of this genomic fragment correlates with the size of the apo(a) protein in different individuals, indicating that different apo(a) alleles posses different numbers of kringle 4-encoding repeats. This discovery provided a molecular handle with which to analyze the apo(a) gene directly, and to examine its role in determining the plasma level of Lp(a) in humans. The investigator has shown in Caucasians that the sequence variation in the apo(a) gene is the most important determinant of plasma Lp(a) levels. The specific questions that the investigator will now address are : 1) Why do plasma levels of Lp(a) vary between Caucasians and African-Americans? 2) How much of this variation is due to differences at the apo(a) locus? 3) What are the structural determinants at the apo(a) locus that affect the plasma level and at the atherogenicity of Lp(a)? 4) And finally, do genes that influence LDL metabolism modulate the levels of plasma Lp(a)? To answer these questions, the investigator will perform : 1) Family studies to determine if the plasma level of Lp(a) segregates with the apo(a) gene in African-Americans; 2) Pedigree analysis to determine the effect of mutations in the LDL receptor and apo(B) genes on the plasma level of Lp(a); 3) Molecular characterization of selected apo(a) alleles which are associated with either high, or low levels of plasma Lp(a); 4) Molecular characterization of apo(a) alleles associated with coronary artery disease; 5) and finally, tissue culture and animal studies designed to express the apo(a) gene in its authentic genomic context. By learning more about the apo(a) gene structure and its relation to the plasma level of Lp(a) the investigator will gain insights into the mechanisms underlying the role of Lp(a) in atherogenesis.