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学家族成员进行分子和临床研究。尽管HDL-C与冠状动脉疾病（CAD）之间的负相关已被充分证明，但遗传基础和潜在的临床意义尚未得到系统的解决。提出的研究的具体目的包括：1)收集和表征极低HDL-C的先证者的血浆和DNA。连锁分析将使用高密度脂蛋白- C候选基因内或附近的高度多态性标记进行。要测试的假设是多态微卫星与低HDL-C表型分离。2)进一步研究与特异性靶1中确定的特定HDL-C候选基因相关的家族遗传特征。待验证的假设是HDL-C候选者的结构变异是导致低HDL-C的原因。3)评估特异性目标2中发现的新基因组变异的生理意义。要验证的假设是结构变异会影响基因产物的表达。4)检查低HDL-C综合征的早期动脉粥样硬化。要检验的假设是，颈动脉内膜-内侧厚度增加是孤立性低HDL-C的普遍现象。识别这种疾病的最极端形式为实现这些基本目标提供了一个独特的机会。因此，进一步了解分离性低HDL-C的分子基础及其潜在的临床后遗症（如CAD），可能有助于制定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.