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

本文采用酶联免疫吸附试验（EIA）技术对32例非糖尿病的原发性IV型高脂蛋白血症患者血浆LPL免疫反应物进行了首次筛查，并采用PCR-SSCP和直接测序法对LPL基因进行了二次筛查，系统地探讨了原发性IV型高脂蛋白血症的病因。通过这种方法，我们发现24名患者（75%的受试患者）具有低LPL质量值（51-129 ng/ml），低于对照LPL质量值的第5百分位数。在24例患者中，18例可用于分析LPL基因畸变。结果发现14例LPL异常为杂合子状态。因此，杂合子LPL缺乏症是原发性IV型高脂蛋白血症的潜在遗传性疾病。LPL基因的5种常见多态性（HindIII、HinfI、MaeII、PvuII和tetrarepeat）以及由这5种常见多态性构建的单倍型均不影响LPL质量值。LPL质量水平低于第5百分位数的受试者在与甘油三酯合成刺激因素如高酒精摄入相结合时易于表现为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子，则测定血浆LPL质量水平和/或早期诊断杂合子LPL缺乏将有助于预防老年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.