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Elucidation of an underlying etiology of atherogenic type IV hyperlipoproteinemia and development of its genetic diagnostic method

阐明致动脉粥样硬化 IV 型高脂蛋白血症的潜在病因及其遗传诊断方法的开发

基本信息

批准号：
06670179
负责人：
TAKAGI Atsuko
金额：
$ 1.34万
依托单位：
NATIONAL CARDIOVASCULAR CENTER RESEARCH INSTITUTE
依托单位国家：
日本
项目类别：
Grant-in-Aid for General Scientific Research (C)
财政年份：
1994
资助国家：
日本
起止时间：
1994 至 1995
项目状态：
已结题

项目摘要

We have systematically investigated an underlying etiology of primary type IV hyperlipoproteinemia by monitoring LPL immunoreactive mass in postheparin plasma of 32 non diabetic patients with primary type IV hyperlipoproteinemia using our sandwich-EIA technique for the first screening, follwed by a second screening for LPL gene aberrations using PCR-SSCP and direct sequencing methods improved by us. By this approach, we found that 24 patients (75% of the tested patients) had low LPL mass values (51-129 ng/ml) which is lower than the 5th percentile of control LPL mass values. Of the 24 patients, 18 were available for analyzing LPL gene aberrations. We found 14 patients had LPL aberrations in heterozygous state. Thus heterozygous LPL deficiency is an underlying genetic disorder of primary type IV hyperlipoproteinemia. The five common polymorphisms (HindIII,HinfI,MaeII,PvuII and tetrarepeat) on LPL gene and haplotypes which were constructed with the five common polymorphisms did not affect LPL mass values. Subjects whose LPL mass level is lower than 5th percentile are prone to manifest type IV hyperlipoproteinemia when this is coupled with triglyceride synthesis stimulating factors like high alcohol intake. The measurement of plasma LPL mass levels and/or early diagnosis of heterozygous LPL deficiency will help to prevent the manifestation of type IV hyperlipoproteinemiain old age, if the subjects improve lifestyle as well as superimposing triglyceride synthesisstimulating factors.

我们系统地研究了原发性 IV 型高脂蛋白血症的潜在病因学，通过使用我们的夹心 EIA 技术进行第一次筛查，监测 32 名患有原发性 IV 型高脂蛋白血症的非糖尿病患者肝素后血浆中的 LPL 免疫反应性质量，随后使用 PCR-SSCP 和我们改进的直接测序方法对 LPL 基因畸变进行第二次筛查。通过这种方法，我们发现 24 名患者（占测试患者的 75%）的 LPL 质量值较低（51-129 ng/ml），低于对照 LPL 质量值的第 5 个百分位数。在这 24 名患者中，有 18 名可用于分析 LPL 基因畸变。我们发现 14 名患者在杂合状态下存在 LPL 畸变。因此，杂合 LPL 缺陷是原发性 IV 型高脂蛋白血症的潜在遗传性疾病。 LPL基因上5种常见多态性(HindIII、HinfI、MaeII、PvuII和tetrarepeat)以及用这5种常见多态性构建的单倍型不影响LPL质量值。 LPL 质量水平低于第 5 个百分位数的受试者在与高酒精摄入等甘油三酯合成刺激因素相结合时容易出现 IV 型高脂蛋白血症。如果受试者改善生活方式并叠加甘油三酯合成刺激因素，血浆LPL质量水平的测量和/或杂合LPL缺乏的早期诊断将有助于预防老年IV型高脂蛋白血症的表现。