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(Arteriosclerosis, Thrombosis, and Vascular Biology. 1997;17:741-747.)
© 1997 American Heart Association, Inc.

Articles

Phenotypic Variation in Patients Heterozygous for Familial Defective Apolipoprotein B (FDB) in Three European Countries

P.S. Hansen; J.C. Defesche; J.J.P. Kastelein; L.U. Gerdes; L. Fraza; C. Gerdes; F. Tato; H.K. Jensen; L.G. Jensen; I.C. Klausen; O. Faergeman; ; H. Schuster

From the Department of Internal Medicine and Cardiology A, University Hospital of Aarhus, Denmark (P.S.H., L.U.G., C.G., H.K.J., L.G.J., I.C.K., O.F.); the Department of Vascular Medicine, Academic Medical Centre, University of Amsterdam, The Netherlands (J.C.D., J.J.P.K., L.F.); the Medizinische Poliklinik, Ludwig-Maximilians-Universität, Munich (F.T.), and the Franz-Volhard-Klinik, Freie Universität Berlin (H.S.), Germany.

Correspondence to Peter Steen Hansen, MD, PhD, Department of Internal Medicine and Cardiology A, Aarhus Amtssygehus, Tage-Hansens Gade 2, DK-8000 Aarhus C, Denmark.

Abstract A glutamine-for-arginine substitution at amino acid position 3500 of apolipoprotein B (apo B) causes synthesis of LDL with reduced binding affinity to the LDL receptor (LDLR). The associated clinical syndrome has been named familial defective apolipoprotein B-100 (FDB). In 205 FDB patients from Germany (n=73), the Netherlands (n=87), and Denmark (n=45), we tried to assess determinants of variation in lipid concentrations. Besides age, sex, and geographic origin, variation in the LDLR gene was the most powerful determinant of variation in total cholesterol and LDL cholesterol levels. Polymorphic variation in the LDLR gene (SfaNI, exon 2; Nco I, exon 18) was associated with total cholesterol (TC) and LDL cholesterol (LDL-C) variation in women (SfaNI: P=.04 and .03 for TC and LDL-C, respectively; Nco I: P=.003 and .006, respectively), whereas the Ava II (exon 13) and the Pvu II (intron 15) polymorphisms were not. Combined information from all three LDLR exon polymorphisms showed that subjects with at least one S+A+N+ allele had 13% to 20% higher TC than non-S+A+N+ subjects (P=.02 [TC, men]; P=.01 [LDL-C, men]; P=.005 [TC, women]; and P=.004 [LDL-C, women]) and, together with age and geographic origin, accounted for 20% (women) and 19% (men) of the variation in LDL-C. The expected association of the apo E genotypes (e₃e₂, e₃e₃, and e₃e₄) with cholesterol concentrations was seen in S+A+N+ but not in non-S+A+N+ subjects and in P-P- but not in P+P+ or P+P- subjects. With regard to clinical expression, FDB patients had lower TC and LDL-C levels and a lower prevalence of cardiovascular disease than 101 Danish patients with familial hypercholesterolemia.

Key Words: familial defective apolipoprotein B • genetics • familial hypercholesterolemia • low-density lipoprotein receptor • lipoprotein lipase • apolipoprotein B • apolipoprotein E

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