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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1999;19:1306-1315.)
© 1999 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Effects of a Frequent Apolipoprotein E Isoform, ApoE4_Freiburg (Leu28Pro), on Lipoproteins and the Prevalence of Coronary Artery Disease in Whites

Matthias Orth; Wei Weng; Harald Funke; Armin Steinmetz; Gerd Assmann; Matthias Nauck; Jutta Dierkes; Andreas Ambrosch; Karl H. Weisgraber; Robert W. Mahley; Heinrich Wieland; Claus Luley

From the Institut für Klinische Chemie und Pathobiochemie, Universität Magdeburg (M.O., J.D., A.A., C.L.), Institut für Klinische Chemie und Laboratoriumsmedizin, Universität Münster (W.W., H.F., G.A.), Abteilung für Endokrinologie und Stoffwechsel, Universität Marburg (A.S.), and Abteilung für Klinische Chemie, Universität Freiburg, Germany (M.O., M.N., H.W., C.L.); Gladstone Institute of Cardiovascular Disease, San Francisco (M.O., K.H.W., R.W.M.), Cardiovascular Research Institute (M.O., K.H.W., R.W.M.), and Departments of Medicine (R.W.M.) and Pathology (K.H.W., R.W.M.), University of California, San Francisco. Current address for Wei Wang Laboratory of Biochemical Genetics and Metabolism, The Rockefeller University, New York, NY 10021-6399.

Correspondence to Dr Matthias Orth, Universitätsklinikum Benjamin Franklin, Freie Universität, Institut für Klinische Chemie und Pathobiochemie (WE 13), Hindenburgdamm 30, D-12220 Berlin, Germany. E-mail orth{at}ukbf.fu-berlin.de

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.

Key Words: apoE polymorphism • mutation • atherosclerosis • isoelectric focusing

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