Effects of a Frequent Apolipoprotein E Isoform, ApoE4 Freiburg (Leu28→Pro), on Lipoproteins and the Prevalence of Coronary Artery Disease in Whites

Abstract

Abstract —Different isoforms of apoE modulate the concentrations of plasma lipoproteins and the risk for atherosclerosis. A novel apoE isoform, apoE4 Freiburg , was detected in plasma by isoelectric focusing because its isoelectric point is slightly more acidic than that of apoE4. ApoE4 Freiburg results from a base exchange in the APOE4 gene that causes the replacement of a leucine by a proline at position 28. Analysis of the allelic frequencies in whites in southwestern Germany revealed that this isoform is frequent among control subjects (10:4264 alleles) and is even more frequent in patients with coronary artery disease (21:2874 alleles; P =0.004; adjusted odds ratio, 3.09; 95% confidence interval, 1.20 to 7.97). ApoE4 Freiburg affects serum lipoproteins by lowering cholesterol, apoB, and apoA-I compared with apoE4 ( P <0.05). Our 4 apoE4 Freiburg homozygotes suffered from various phenotypes of hyperlipoproteinemia (types IIa, IIb, IV, and V). In vitro binding studies excluded a binding defect of apoE4 Freiburg , and in vivo studies excluded an abnormal accumulation of chylomicron remnants. ApoE4 Freiburg and apoE4 accumulated to a similar extent in triglyceride-rich lipoproteins. HDLs, however, contained about 40% less apoE4 Freiburg than apoE4. In conclusion, our data indicate that apoE4 Freiburg exerts its possible atherogenic properties by affecting the metabolism of triglyceride-rich lipoproteins and HDL.