Abnormal interaction between low density lipoprotein receptors (LDLR) and their ligands, apolipoprotein E and B, causes decreased catabolism of lipoproteins which carry these apolipoproteins (VLDL, IDL and/or LDL) and thereby increased plasma concentrations of these. In familial hypercholesterolemia (FH), abnormal interaction is due to mutations in the LDLR gene, and in type III hyperlipidemia due to mutations in the apo E gene. A few mutations in the apolipoprotein B (apo B) gene have been described, of which the apo B-3,500 Arg-Gln seems by far the most frequent, that causes defective binding to normal LDLR. The metabolic disorder associated with these mutations has been named familial defective apolipoprotein B-100 (FDB). The frequency of the apo B-3,500 Arg-Gln mutation is particularly high in Central Europe (Switzerland) with lower frequencies south of the Alpes, in Russia and in Scandinavia. We found an incidence of 1/1250 of the mutation in Denmark (III), employing a DNA based assay optimized to allow detection of the mutation in very small amounts of DNA (I). Since other mutations in the receptor binding domain of the apo B-100 have been described, we developed another DNA based assay, employing DGGE technique, to screen for other mutations in the region of amino acid 3,456 to 3,553 (II). However, no other mutations but the apo B-3,500 Arg-Gln have so far been detected in Danish hypercholesterolemic patients. In a study of 5 Danish families with FDB (46 heterozygous FDB patients and 57 unaffected relatives) we found that FDB patients had significantly increased mean cholesterol and LDL cholesterol concentrations, but with a wide range of variation and with approximately 30% having cholesterol concentrations below the 95th percentile for the general population (IV). This was confirmed in a compilation of data on 205 FDB patients from the Netherlands, Germany and Denmark (V). In this study we also compared the biochemical and clinical features of FDB with those of 101 Danish FH patients in whome FDB had been ruled out. Our data support, that the LDL cholesterol elevation is less pronounced in FDB than in FH and that the age-specific prevalence of atherosclerotic cardiovascular disease (CVD) is lower in FDB than in FH. In the compiled study of 205 FDB heterozygotes (V), we found that age, gender and genetic variation in the LDLR gene explained a considerable part of the between-individual variation in total and LDL cholesterol. We conducted a prospective study of the lipid lowering effect of pravastatin and gemfibrozil in 30 Danish FDB patients (VI). Together with other, retrospective, studies, we conclude that the cholesterol lowering effect of HMG-coA-reductase inhibitors, anion binding resins and nicotinic acid is fully comparable to that observed when treating FH patients and type IIa hypercholesterolemic patients, without clinical signs of FH.