PHENOTYPIC VARIATION IN PATIENTS HETEROZYGOUS FOR FAMILIAL DEFECTIVE APOLIPOPROTEIN-B (FDB) IN 3 EUROPEAN COUNTRIES

A glutamine-for-arginine substitution at amino acid position 3500 of a polipoprotein B (apo B) causes synthesis of LDL with reduced binding a ffinity to the LDL receptor (LDLR). The associated clinical syndrome h as been named familial defective apolipoprotein B-100 (FDB). In 205 FD B patients from Germany (n=73), The Netherlands (n=87), and Denmark (n =45), we tried to assess determinants of variation in lipid concentrat ions. Besides age, sex, and geographic origin, variation in the LDLR g ene was the most powerful determinant of variation in total cholestero l 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, respectivel y), whereas the Ava II (exon 13) and the Pvu II (intron 15) polymorphi sms were not. Combined information from all three LDLR exon polymorphi sms 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, m en]; 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 genotyp es (e(3)e(2), e(3)e(3), and e(3)e(4)) 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 pati ents had lower TC and LDL-C levels and a lower prevalence of cardiovas cular disease than 101 Danish patients with familial hypercholesterole mia.