MOLECULAR & CLINICAL EVALUATION OF LOW HDL SYNDROMES

该研究计划的总体目标是对低水平高密度脂蛋白胆固醇(HDL-C)的受试者和受影响的生物家庭成员进行分子和临床研究。尽管高密度脂蛋白胆固醇与冠状动脉疾病(CAD)之间的负相关已经得到了很好的证明，但其遗传基础和潜在的临床意义还没有得到系统的解决。拟议研究的具体目标包括：1)从高密度脂蛋白胆固醇水平极低的先证者身上收集血浆和DNA并进行鉴定。将使用高密度脂蛋白胆固醇候选基因内部或附近的高度多态标记进行连锁分析。需要检验的假设是，多态微卫星与低高密度脂蛋白-C表型分离。2)有证据表明与特定目标中确定的特定高密度脂蛋白胆固醇候选基因连锁的家系的进一步遗传特征1.待检验的假设是高密度脂蛋白胆固醇候选基因中的结构变异是导致低高密度脂蛋白胆固醇的原因3)评估在特定目的中发现的新的基因组变异的生理意义2.待检验的假设是结构变异将影响基因产物的表达。4)低高密度脂蛋白胆固醇综合征早期动脉粥样硬化的检测。需要检验的假设是，孤立的低高密度脂蛋白胆固醇患者普遍存在颈动脉内膜-中层厚度增加。确定这种疾病的最极端形式为解决这些基本目标提供了一个独特的机会。因此，进一步了解孤立的低高密度脂蛋白胆固醇及其潜在的临床后遗症(如冠心病)的分子基础，可能有助于开发有效治疗这种疾病的治疗策略。

The overall aim of the research proposal is to perform molecular and clinical studies in subjects and affected biologic family members with low levels of high density lipoprotein cholesterol (HDL-C). Whereas an inverse association between HDL-C and coronary artery disease (CAD) is well documented, the genetic basis and potential clinical implications have not been systematically addressed. The specific aims of the proposed research include: 1) Collection and characterization of plasma and DNA from probands with very low HDL-C. Linkage analysis will be performed using highly polymorphic markers within or near HDL- C candidate genes. The hypothesis to be tested is that polymorphic microsatellites segregate with the low HDL-C phenotype. 2) Further genetic characterization of families with evidence of linkage to specific HDL-C candidate genes identified in Specific Aim 1. The hypothesis to be tested is that structural variants in HDL-C candidates are responsible for low HDL-C. 3) Evaluate the physiologic significance of novel genomic variants identified in Specific Aim 2. The hypothesis to be tested is that structural variants will affect expression of the gene product. 4) Examine early atherosclerosis in low HDL-C syndromes. The hypothesis to be tested is that increased carotid intima-medial thickness is prevalent with isolated low HDL-C. Identification of the most extreme forms of this disorder provides a unique opportunity to address these fundamental objectives. Further understanding of the molecular basis of isolated low HDL-C and its potential clinical sequelae (e.g., CAD), may therefore aid in the development of therapeutic strategies to effectively treat this disorder.