PATHOBIOLOGICAL DETERMINANTS OF ATHEROSCLEROSIS IN YOUTH

拟议研究的总体目标是确定具体的 参与动脉病变发病机制的基因。这个 建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 确定与疾病范围和性质相关的风险因素 动脉粥样硬化病变。这项提议是对以下问题的回应 检讨委员会就第一阶段的建议 包括遗传分析的多中心研究(使用限制 片段长度多态，RFLP)将检测到 特定基因与动脉粥样硬化形成的关系。长的- 多中心研究的短期目标是：(1)明确更多 准确地说，动脉病变的发育过程 儿童期晚期(脂肪条纹)逐渐形成的特征 与动脉粥样硬化相关的晚期病变(纤维斑块) 成年期，以及(2)与选定的危险因素(血清 胆固醇)和脂蛋白浓度，吸烟， 血压、糖尿病和肥胖症)到 年轻人的动脉粥样硬化病变。 这项拟议研究的目的与第二个目标有关。 包括：(1)确定 每名受试者的RFLP基因分型 载脂蛋白和低密度脂蛋白受体基因(Southern印迹分析 从每个采集中心送来的肝脏样本的DNA)，(2) 载脂蛋白E亚型基因分型的研究 寡核苷酸探针，以及(3)检测 动脉病变范围和特点的RFLP基因分型 在年轻人身上。检测到关联的RFLP不仅 为遗传中介致病机制提供证据 动脉损伤，但确定哪个基因(S)负责 动脉粥样硬化的潜在分子过程。要最大化地 检测到与致病相关的RFLP的概率 在动脉病变中，特定的RFLP选自 发表了来自其他人类研究对象的报告。大部分 这些RFLP此前曾与心脏病有关 或改变血脂和脂蛋白水平。这项建议 为遗传研究提供了一个独特而重要的扩展。 心脏病，并将第一次直接检查的 特异性基因在动脉粥样硬化早期的作用 年轻人的皮损。

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.