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

我们系统地研究了原发性IV型高脂蛋白血症的潜在病因，通过使用我们的三明治- eia技术对32例原发性IV型高脂蛋白血症非糖尿病患者的肝素后血浆中的LPL免疫反应团进行了第一次筛选，随后使用我们改进的PCR-SSCP和直接测序方法对LPL基因畸变进行了第二次筛选。通过这种方法，我们发现24例患者（75%的检测患者）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。24例患者中，18例可用于分析LPL基因畸变。我们发现14例患者存在杂合状态的LPL畸变。因此杂合性LPL缺乏症是原发性IV型高脂蛋白血症的一种潜在遗传疾病。LPL基因上的5个常见多态性（HindIII、HinfI、MaeII、PvuII和tetrarepeat）以及用这5个常见多态性构建的单倍型对LPL质量值没有影响。LPL质量水平低于第5百分位的受试者，当伴有高酒精摄入量等刺激甘油三酯合成的因素时，容易出现IV型高脂蛋白血症。测量血浆LPL质量水平和/或早期诊断杂合性LPL缺乏，如果受试者改善生活方式并叠加甘油三酯合成刺激因子，将有助于预防老年期IV型高脂蛋白血症的表现。

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.