PATHOBIOLOGICAL DETERMINANTS OF ATHEROSCLEROSIS IN YOUTH

拟议研究的总体目标是确定具体的 介导动脉病变发病机制的基因。 的 拟议的研究是一项多中心研究的一部分， 3000名年轻人（15-34岁）的动脉病变， 确定与风险程度和性质有关的风险因素， 动脉粥样硬化病变 这项建议是为了回应 第一阶段审查委员会的建议 多中心研究，包括遗传分析（使用限制 片段长度多态性，RFLPs），将检测 特定基因与动脉粥样硬化形成之间的关系。 很长的- 多中心研究的长期目标是：（1）定义更多 正是动脉损伤的发展过程 儿童晚期的特征（脂肪条纹）进展形成 与动脉粥样硬化相关的晚期病变（纤维斑块） 在成年期，和（2）相关的选定的危险因素（血清 胆固醇）和脂蛋白浓度，吸烟， 血压、糖尿病和肥胖症）的特征， 年轻人的动脉粥样硬化病变。 本研究的目的与第二个目标有关 包括：（1）确定 每个受试者的RFLPs基因型， 载脂蛋白和LDL受体基因（Southern印迹分析 来自每个收集中心的肝脏样本的DNA），（2） 使用载脂蛋白E亚型基因型对受试者进行分型 寡核苷酸探针，和（3）检查的影响， RFLP基因型与动脉病变程度和特征的关系 在年轻人中。 相关RFLP的检测不仅 提供了证据，遗传媒介的发病机制， 动脉病变，但确定哪个基因是负责 动脉粥样硬化的潜在分子过程。 最大化 检测与发病机制相关的RFLPs的概率 在动脉病变中，特异性RFLPS选自 发表了其他人类研究的报告。 大部分 这些RFLP以前与心脏病有关， 或改变的血清脂质和脂蛋白水平。 这项建议 为遗传学研究提供了一个独特而重要的延伸， 心脏病，并将是第一次直接检查， 特定基因在动脉粥样硬化早期阶段的作用 年轻人的病变。

The overall goal of the proposed research is to identify specific genes that mediate the pathogenesis of arterial lesions. The proposed research is part of a multicenter study to examine arterial lesions in 3000 young persons (15-34 years), and to identify risk factors that are associated with extent and nature of atherosclerotic lesions. This proposal is in response to recommendations of the review committee for phase I of the multicenter study to include genetic analyses (using restriction fragment length polymorphisms, RFLPs) that will detect associations between specific genes and atherogenesis. The long- term objectives of the multi-center study are: (1) to define more precisely the developmental processes by which arterial lesions characteristic of late childhood (fatty streaks) progress to form advanced lesions (fibrous plaques) associated with atherosclerosis in adulthood, and (2) to relate selected risk factors (serum cholesterol) and lipoprotein concentrations, cigarette smoking, blood pressure, diabetes, and obesity) to characteristics of atherosclerotic lesions in young persons. The aims of this proposed research relate to the second objective of the multi-center study and include: (1) determination of genotypes for each subject with respect to RFLPs in apolipoprotein and the LDL receptor genes (Southern blot analyses of DNA from liver samples sent from each collection center), (2) typing of subjects for apo E isoform genotypes using oligonucleotide probes, and (3) examination of the effects of RFLP genotypes on extent and characteristics of arterial lesions in young people. Detection of an associated RFLP not only provides evidence for genetic mediation of the pathogenesis of arterial lesions, but identifies which gene(s) is responsible for the underlying molecular processes of atherosclerosis. To maximize the probability of detecting RFLPs associated with pathogenesis of arterial lesions, specific RFLPS have been selected from published reports from other studies of human subjects. Most of these RFLPs have previously been associated with heart disease or altered levels of serum lipids and lipoproteins. This proposal presents a unique and important extension to genetic studies of heart disease, and will be the first direct examination of the effects of specific genes on the early stages of atherosclerotic lesions in young persons.