MOLECULAR & CLINICAL EVALUATION OF LOW HDL SYNDROMES

该研究提案的总体目标是在受试者和受影响的低水平高密度脂蛋白胆固醇（HDL-C）生物家族成员中进行分子和临床研究。 尽管HDL-C和冠状动脉疾病（CAD）之间的负相关性已被充分证明，但遗传基础和潜在的临床意义尚未得到系统的解决。本研究的具体目的包括：1）从极低HDL-C先证者中收集血浆和DNA并进行表征。 将使用HDL-C候选基因内或附近的高度多态性标记进行连锁分析。 待检验的假设是多态性微卫星与低HDL-C表型分离。 2)进一步的家族遗传特征分析，有证据表明与特定目标1中确定的特定HDL-C候选基因存在连锁关系。待检验的假设是HDL-C候选者中的结构变异是低HDL-C的原因。 3)评价特异性目标2中鉴定的新型基因组变异的生理学意义。 待检验的假设是结构变异将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。待检验的假设是颈动脉内膜中层厚度增加在孤立性低HDL-C患者中普遍存在。确定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。 进一步了解孤立性低HDL-C的分子基础及其潜在的临床后遗症（例如，CAD），因此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.