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Control mechanisms for expression of apolipoprotein (a) gene, a risk factor of thrombosis.

载脂蛋白 (a) 基因（血栓形成的危险因素）表达的控制机制。

基本信息

批准号：
05454327
负责人：
ICHINOSE Akitada
金额：
$ 4.16万
依托单位：
Yamagata Universtity
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (B)
财政年份：
1993
资助国家：
日本
起止时间：
1993 至 1994
项目状态：
已结题

项目摘要

Concentration of lipoprotein (a) in plasma is inherited in an autosomal codominant manner and its high concentration leads to atherothrombotic disease. Nucleotide sequence analysis of the apolipoprotein (a) gene revealed the presence of polymorphisms in its 5'-flanking region, which can be analyzed by in vitro amplification employing gene-specific primers. Genomic DNAs from normal individuals have been subclassified into four alleles according to the patterns of restriction digestion. The ratios of these subtypes differed between Caucasians and Japanese, and in patients with myocardial infarction. The differences in the nucleotide sequence of the 5'-regulatory region may lead to differential transcriptional efficiency, which in turn results in a wide variety of plasma Lp (a) levels, not only among individuals but also between ethnic groups. This hypothesis was confirmed by the CAT (chloramphenicol acethyltransferase) assay when each of the four types of 5'-alleles had been inserted into a promoterless CAT vector and its transcriptional activity had been compared directly. There was 3-fold difference in transcriptional activities between the highest type C and the lowest type D when the activity of type A was defined as 100%. These results will contribute to understanding of molecular mechanisms of atherothrombotic disease, and to development of genetic diagnosis and treatment of hyperlipoprotein (a) emia in the near future.

血浆中脂蛋白(a)的浓度以常染色体共显性方式遗传，其高浓度可导致动脉粥样硬化血栓性疾病。载脂蛋白(a)基因的核苷酸序列分析显示其5'侧区存在多态性，可以通过基因特异性引物体外扩增进行分析。正常人的基因组dna根据酶切的模式被细分为四种等位基因。这些亚型的比例在白种人和日本人之间以及心肌梗死患者之间存在差异。5'-调控区核苷酸序列的差异可能导致转录效率的差异，这反过来导致血浆Lp (a)水平的差异，不仅在个体之间，而且在种族之间。将四种类型的5’等位基因分别插入无启动子的CAT载体并直接比较其转录活性，通过CAT （chloramphenicol acetyltransferase）实验证实了这一假设。当A型活性为100%时，最高的C型与最低的D型之间的转录活性差异为3倍。这些结果将有助于了解动脉粥样硬化性血栓疾病的分子机制，并有助于在不久的将来发展高脂蛋白(a)血症的遗传诊断和治疗。