de Knijff P, van den Maagdenberg A M, Stalenhoef A F, Leuven J A, Demacker P N, Kuyt L P, Frants R R, Havekes L M
Institute of Ageing and Vascular Research, Netherlands Organization for Applied Scientific Research, Leiden.
J Clin Invest. 1991 Aug;88(2):643-55. doi: 10.1172/JCI115349.
By the careful screening of familial dysbetalipoproteinemic (FD) patients, five probands showing heterozygosity for the APOE3-Leiden allele were found. Genealogical studies revealed that these probands share common ancestry in the 17th century. In a group of 128 family members, spanning three generations, 37 additional heterozygous APOE3-Leiden gene carriers were detected. Although with a variable degree of severity, all carriers exhibited characteristics of FD such as (a) elevated levels of cholesterol in the very low density lipoprotein (VLDL) and intermediate density lipoprotein (IDL) fractions, (b) elevated ratios of cholesterol levels in these density fractions over total plasma levels of triglycerides, and (c) strongly increased plasma levels of apolipoprotein E (apoE). Multiple linear regression analysis revealed that most of the variability in expression of FD in APOE3-Leiden allele carriers can be explained by age. Body mass index showed a less significant influence on the expression of FD. Gender had no effect on the expression in E3-Leiden allele carriers, nor did it influence the age of onset of FD. In the group of APOE3-Leiden allele carriers, we found that the E2 allele enhances the expression of FD, whereas the E4 allele had the opposite effect. Isoelectric focusing of plasma and of isolated VLDL, IDL, and high density lipoprotein density fractions showed that in E3-Leiden allele carriers the apoE3-Leiden variant largely predominates over its normal apoE counterpart, especially in the VLDL and IDL density fractions. We conclude that in APOE*3-Leiden allele carriers FD is dominantly inherited with a high rate of penetrance, i.e., the presence of normally functioning apoE molecules in the plasma does not prevent the age-related expression of this disease.
通过对家族性异常β脂蛋白血症（FD）患者进行仔细筛查，发现了5名携带APOE3 - 莱顿等位基因杂合性的先证者。系谱研究表明，这些先证者在17世纪有共同的祖先。在一个涵盖三代人的128名家庭成员群体中，又检测到37名额外的APOE3 - 莱顿基因杂合携带者。尽管严重程度各不相同，但所有携带者均表现出FD的特征，如：（a）极低密度脂蛋白（VLDL）和中间密度脂蛋白（IDL）组分中的胆固醇水平升高；（b）这些密度组分中的胆固醇水平与血浆甘油三酯总水平的比值升高；（c）载脂蛋白E（apoE）的血浆水平大幅升高。多元线性回归分析显示，APOE3 - 莱顿等位基因携带者中FD表达的大部分变异性可由年龄来解释。体重指数对FD表达的影响较小。性别对E3 - 莱顿等位基因携带者的表达没有影响，也不影响FD的发病年龄。在APOE3 - 莱顿等位基因携带者群体中，我们发现E2等位基因增强了FD的表达，而E4等位基因则有相反的作用效果。血浆以及分离出的VLDL、IDL和高密度脂蛋白密度组分的等电聚焦显示，在E3 - 莱顿等位基因携带者中，apoE3 - 莱顿变体在很大程度上比其正常的apoE对应物占优势，尤其是在VLDL和IDL密度组分中。我们得出结论，在APOE*3 - 莱顿等位基因携带者中，FD以高外显率显性遗传，即血浆中正常功能的apoE分子的存在并不能阻止该疾病与年龄相关的表达。
