DIFFERENCES IN THE PHENOTYPIC CHARACTERISTICS OF SUBJECTS WITH FAMILIAL DEFECTIVE APOLIPOPROTEIN B-100 AND FAMILIAL HYPERCHOLESTEROLEMIA

Familial defective apolipoprotein B-100 (FDB) is a recently identified autosomal-dominantly inherited disorder caused by a point mutation in the apolipoprotein (apo) B gene. To determine whether the phenotypic characteristics in FDB subjects are similar to those in subjects with familial hypercholesterolemia (FH), 76 kindreds fulfilling the clinica l criteria for heterozygous FH/FDB were characterized using molecular biological techniques. Allele-specific polymerase chain reaction (PCR) at the apoB locus was used for diagnosis or exclusion of FDB. PCR-bas ed methods for detection of two point mutations (V408M and P664L) at t he LDL receptor (LDLR) locus, cosegregation analysis using eight restr iction fragment length polymorphisms (RFLPs) at the LDLR locus, or the exclusion of FDB confirmed the clinical diagnosis of FH. Three kindre ds were not included because of a missing cosegregation between a part icular haplotype and the FH phenotype. We predicted that a similar num ber of kindreds would be detected in the two groups, assuming comparab le prevalences of the diseases in our population and similar phenotypi c characteristics. However, only nine kindreds were identified with th e FDB mutation compared with 64 kindreds with FH (P<.0001). From these 73 kindreds, 28 FDB heterozygotes and 129 FH heterozygotes were compa red using multivariate analysis. There were no differences between the se two groups with respect to age, sex, and apoE genotype distribution , lipoprotein(a) concentrations, body mass index, blood pressure, and smoking habits. However, FDB subjects demonstrated significantly lower concentrations of total cholesterol (8.1 versus 10.2 mmol/L, P<.001), LDL cholesterol (6.3 versus 8.2 mmol/L, P<.001), and triglycerides (1 .3 versus 1.8 mmol/L, P=.025) and higher concentrations of HDL cholest erol (1.4 versus 1.2 mmol/L, P=.015) than subjects with FH. In contras t to FH, female FDB subjects tended to have higher concentrations of t otal cholesterol (8.9 versus 7.5 mmol/L, P=.032) and LDL cholesterol ( 7.1 versus 5.7 mmol/L, P=.026) than FDB males. The same results regard ing total and LDL cholesterol and sex differences were observed when i ndividual data of 238 FDB and 415 FH subjects from the literature were compared. In addition, FDB subjects showed much larger total choleste rol fluctuations than FH subjects (median of intraindividual coefficie nts of variation: FDB, 14.5%. FH, 5.3%; P<.001). In summary, these res ults demonstrate that FDB subjects tend to have a milder form of hyper lipoproteinemia than FH subjects and that only a part of the subjects with FDB fulfill the established criteria for identifying FH.