Hazzard W R, Goldstein J L, Schrott M G, Motulsky A G, Bierman E L
J Clin Invest. 1973 Jul;52(7):1569-77. doi: 10.1172/JCI107333.
Although analysis of lipoprotein phenotypes is widely used to diagnose and classify the familial hyperlipidemias, an evaluation of this system as a method for genetic classification has hitherto not been published. The present study of 156 genetically defined survivors of myocardial infarction was therefore designed to examine the relationship between lipoprotein phenotypes and genetic lipid disorders. The lipoprotein phenotypes of each survivor was determined primarily by measurement of his plasma triglyceride and low density lipoprotein (LDL)-cholesterol concentrations; his genetic disorder was identified by analysis of whole plasma cholesterol and triglyceride levels in relatives. The mean levels of LDL-cholesterol discriminated statistically among the three monogenic lipid disorders; it was highest in survivors with familial hypercholesterolemia (261+/-61 mg/100 ml [mean +/-SD]); intermediate in those with familial combined hyperlipidemia (197+/-50); and lowest in those with familial hypertriglyceridemia (155+/-36) (P < 0.005 among the three groups). However, on an individual basis no lipoprotein pattern proved to be specific for any particular genetic lipid disorder; conversely, no genetic disorder was specified by a single lipoprotein pattern. This lack of correlation occurred for the following reasons: (a) individual LDL-cholesterol levels frequently overlapped between disorders; (b) in many instances a small quantitative change in the level of either LDL-cholesterol or whole plasma triglyceride caused qualitative differences in lipoprotein phenotypes, especially in individuals with familial combined hyperlipidemia, who showed variable expression (types IIa, IIb, IV, or V); (c) lipoprotein phenotypes failed to distinguish among monogenic, polygenic, and sporadic forms of hyperlipidemia; (d) clofibrate treatment of some survivors with genetic forms of hyperlipidemia caused their levels of triglyceride and LDL-cholesterol to fall below the 95th percentile, thus resulting in a normal phenotype; and (e) beta-migrating very low density lipoproteins (beta-VLDL), previously considered a specific marker for the type III hyperlipidemic disorder, was identified in several survivors with different lipoprotein characteristics and familial lipid distributions. These studies indicate that lipoprotein phenotypes are not qualitative markers in the genetic sense but instead are quantitative parameters which may vary among different individuals with the same genetic lipid disorder. It would therefore seem likely that a genetic classification of the individual hyperlipidemic patient with coronary heart disease made from a quantitative analysis of lipid levels in his relatives may provide a more meaningful approach than determination of lipoprotein phenotypes.
虽然脂蛋白表型分析被广泛用于家族性高脂血症的诊断和分类，但作为一种基因分类方法，该系统的评估迄今尚未发表。因此，本研究对156名经基因定义的心肌梗死幸存者进行了设计，以研究脂蛋白表型与遗传性脂质紊乱之间的关系。每个幸存者的脂蛋白表型主要通过测量其血浆甘油三酯和低密度脂蛋白（LDL）胆固醇浓度来确定；通过分析亲属的全血浆胆固醇和甘油三酯水平来确定其遗传性疾病。LDL胆固醇的平均水平在三种单基因脂质紊乱之间有统计学差异；在家族性高胆固醇血症幸存者中最高（261±61mg/100ml[平均值±标准差]）；在家族性混合性高脂血症患者中居中（197±50）；在家族性高甘油三酯血症患者中最低（155±36）（三组之间P<0.005）。然而，就个体而言，没有一种脂蛋白模式被证明对任何特定的遗传性脂质紊乱具有特异性；相反，没有一种遗传性疾病由单一的脂蛋白模式确定。缺乏相关性的原因如下：（a）不同疾病之间个体LDL胆固醇水平经常重叠；（b）在许多情况下，LDL胆固醇或全血浆甘油三酯水平的微小定量变化会导致脂蛋白表型的定性差异，特别是在家族性混合性高脂血症患者中，他们表现出可变的表达（IIa、IIb、IV或V型）；（c）脂蛋白表型无法区分单基因、多基因和散发性高脂血症形式；（d）用氯贝丁酯治疗一些患有遗传性高脂血症的幸存者，导致他们的甘油三酯和LDL胆固醇水平降至第95百分位数以下，从而产生正常表型；（e）在一些具有不同脂蛋白特征和家族性脂质分布的幸存者中发现了β迁移极低密度脂蛋白（β-VLDL），以前被认为是III型高脂血症的特异性标志物。这些研究表明，脂蛋白表型在基因意义上不是定性标志物，而是定量参数，在患有相同遗传性脂质紊乱的不同个体之间可能会有所不同。因此，通过对亲属脂质水平进行定量分析对患有冠心病的个体高脂血症患者进行基因分类，可能比确定脂蛋白表型提供一种更有意义的方法。
