APOLIPOPROTEIN A-I GENE POLYMORPHISM AND ATHEROSCLEROSIS

载脂蛋白A-I是血浆高密度脂蛋白的主要蛋白质组分 密度脂蛋白(HDL)。高密度脂蛋白已被证明能促进胆固醇 细胞在体外排出。降低高密度脂蛋白的血浆浓度 胆固醇和载脂蛋白A-I与冠状动脉早发有关 在我们的社会中，动脉粥样硬化导致的疾病(CAD)。遗传性高密度脂蛋白 缺乏症(家族性低脂蛋白血症)似乎相当常见 在早产儿冠心病患者中。载脂蛋白A-I的基因已经被分离出来 特色化的。我们的初步研究表明，特定的载脂蛋白A-I Pst I酶切后检测到的基因多态性 利用特定的探针，在患有 早产儿冠心病(32.8%)高于正常对照组(3.9%)，部分患者 血缘关系与遗传性高密度脂蛋白缺乏症有关。这个载脂蛋白A-I基因 多态是由于apoA-I、apoC-III基因间的变化引起的 区域，靠近ApoA-I编码区的3‘端。 我们的具体目标是：1)确定遗传性高密度脂蛋白的患病率 胆固醇和载脂蛋白A-I缺乏症与Pst I载脂蛋白A-I基因多态性 早产儿冠心病患者及其一级亲属利用 标准脂质分析、免疫分析和Southern blotting；2)评估 早发冠心病的风险是否与该基因有关 3)为了确定高密度脂蛋白缺乏之间的关系， Pst I基因多态性与早产儿冠心病的连锁分析 异常apoA-I、apoC-III基因复合体的分离与鉴定 用多种限制性内切酶进行作图研究，并通过克隆和 测序方法。这些研究将使我们能够测试以下内容 假设： 1.Pst I apoA-I基因多态性与遗传性高密度脂蛋白相关 不足和过早的CAD； 2.与Pst I apoA-I基因相关的遗传性高密度脂蛋白缺乏 多态是一种常见的家族性脂蛋白紊乱 早产儿CAD； 3.Pst I apoA-I基因多态是由于Pst I apoA-I基因突变 ApoA-I、apoC-III基因间隔区，直接或间接(通过 连锁多态)影响载脂蛋白A-I的合成。

Apolipoprotein (apo) A-I is the major protein constituent of plasma high density lipoproteins (HDL). HDL has been shown to promote cholesterol efflux from cells in vitro. Decreased plasma concentrations of HDL cholesterol and apoA-I have been associated with premature coronary artery disease (CAD) due to atherosclerosis in our society. Genetic HDL deficiency (familial hypoalphalipoproteinemia) appears to be fairly common in patients with premature CAD. The gene for apoA-I has been isolated and characterized. Our preliminary studies indicate that a specific apoA-I gene polymorphism, detected following Pst I restriction enzyme digestion utilizing a specific probe, is significantly more common in subjects with premature CAD (32.8%) than in normal control subjects (3.9%), and in some kindreds is associated with genetic HDL deficiency. This apoA-I gene polymorphism is due to an alteration in the apoA-I, apoC-III intergenic region, near the 3' end of the coding region for ApoA-I. Our specific aims are: 1) to determine the prevalence of genetic HDL cholesterol and apoA-I deficiency and the Pst I apoA-I gene polymorphism in patients with premature CAD and their first degree relatives utilizing standard lipid analysis, immunoassay and Southern blotting; 2) to assess whether the risk of developing premature CAD is associated with the gene polymorphism; 3) to ascertain the relationship between HDL deficiency, the Pst I gene polymorphism, and premature CAD by linkage analysis; 4) to isolate and characterize the abnormal apoA-I, apoC-III gene complex by gene mapping studies with multiple restriction enzymes, and by cloning and sequencing methods. These studies will allow us to test the following hypotheses: 1. The Pst I apoA-I gene polymorphism is associated with genetic HDL deficiency and premature CAD; 2. Genetic HDL deficiency associated with the Pst I apoA-I gene polymorphism is a common familial lipoprotein disorder in patients with premature CAD; 3. The Pst I apoA-I gene polymorphism is due to a specific mutation in the apoA-I, apoC-III intergenic region, which directly or indirectly (via a linked polymorphism) affects apoA-I synthesis.