Plasma Lipoproteins in Familial Dysbetalipoproteinemia Associated With Apolipoproteins E2(Argl58^Cys), E3-Leiden, and E2(Lysl46^Gln), and Effects of Treatment With Simvastatin

Using a density-gradient ultracentrifugation technique, we analyzed in detail the plasma lipoprotein profiles of 18 patients with familial dysbetalipoproteinemia (FD) who had apolipoprotein (apo) E2(Argl58-»Cys) homozygosity (the E2-158 variant, n=6), apoE3-Leiden heterozygosity (the E3-Leiden variant, n=6), or apoE2(Lysl46—»Gln) heterozygosity (the E2-146 variant, n=6), with average plasma cholesterol concentrations of 8.99±1.34 mmol/L, 9.29±l-55 mmol/L, and 8.46 ±1.10 mmol/L, respectively. No significant differences in sex, age, body mass index, dietary habits, and standard laboratory tests between the three groups were observed. The lipoprotein profiles of all FD patients were characterized by higher concentrations of very-low-density lipoprotein (VLDL) 1, VLDL2, and intermediate-density lipoprotein (IDL) and a higher cholesteryl ester content of VLDL1 and VLDL2 than in 6 normolipidemic control subjects with an average plasma cholesterol concentration of 5.90±0.53 mmol/L. Major differences between the plasma lipoprotein profiles of patients with the E2-158 variant, the E3-Leiden variant, and the E2-146 variant and the normolipidemic control subjects were in IDL cholesterol concentration (1.70±0.26, 1.50±0.26, 1.05±0.36, and 0.47±0.14 mmol/L, respectively), LDL cholesterol concentration (1.83±0.50, 3.09±0.32, 3.79±0.76, and 3.77±0.56 mmol/L, respectively), and the molar ratio of IDL cholesterol Human apolipoprotein (apo) E, a protein of 299 amino acid residues, is a constituent of several plasma lipoproteins, including chylomicrons, very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (DDL), and a subclass of high-density lipoprotein (HDL), HDL1. Three common alleles of apoE at a single gene locus on chromosome 19 code for three isoforms of apoE, apoE2, apoE3, and apoE4, which can be distinguished by isoelectric focusing. Three hoReceived June 22, 1994; revision accepted August 17, 1994. From the Departments of Cardiology (S.-P.Z., T.F.F.P.V., A. Van der L., F.M.Van 't H.), Internal Medicine (A.H.M.S.), and Human Genetics (A.M.J.M. Van den M., R.R.F.), Medical Faculty, University of Leiden, Department of Biochemistry I (A.V.T.), Cardiovascular Research Institute (COEUR), Erasmus University, Rotterdam, and Gaubius Laboratory (J.A.G.L., L.M.H.), IVVO-TNO, Leiden, Netherlands; Cardiovascular Research Laboratory (S.-P.Z.), Second Affiliated Hospital, to LDL cholesterol (0.98±0.28, 0.48±0.04, 0.28±0.09, and 0.12±0.03, respectively). After 10 weeks of simvastatin treatment the concentrations of plasma cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in 3 patients with the E2-158 variant fell significantly, by 46%, 56%, 53%, and 48%, respectively; they also fell in 3 patients with the E3-Leiden variant, by 48%, 54%, 57%, and 52%, respectively, and in 3 patients with the E2-146 variant, by 38%, 55%, 46%, and 35%, respectively. Simvastatin therapy lowered plasma activity of cholesteryl ester transfer protein but had no significant effect on plasma activity of lecithin: cholesterol acyltransferase. It is concluded that patients with FD due to various apoE variants have different lipoprotein profiles, mainly with regard to IDL and LDL levels, although they have a number of similar features of dysbetalipoproteinemia. Simvastatin therapy effectively reduced the plasma concentrations of total cholesterol, VLDL2 cholesterol, IDL cholesterol, and LDL cholesterol in the three groups of patients studied. It is proposed that apoE-dependent defects of the conversion of IDL to LDL may be an important mechanism in the pathophysiology of FD. (ArterioscUr Thromb. 1994;14:1705-1716.)