Inheritance of type-III hyperlipoproteinemia. Lipoprotein patterns in first-degree relatives.

The lipoprotein (LP) patterns were studied in the families of 19 index cases with type-III hyperlipoproteinemia (HLP). Seventy adult first-degree relatives (93% ascertainment) to the 19 probands were analyzed. The diagnosis of HLP type III among the first-degree relatives was based on three criteria, all of which had to be fulfilled to make the diagnosis: (1) presence of a slow-moving band in very-low-density LP (VLDL) on agarose gel electrophoresis migrating in beta or close to beta position; (2) A cholesterol/triglyceride ratio (mg/100 ml: mmoles/liter) in VLDL greater than 29.0; and (3) A "III-index" [cholesterol/triglycerides in VLDL x 10 divided by cholesterol/triglycerides in low-density LP (LDL)] greater than 1.30. When defined according to these criteria there was a marked over-representation of HLP type III among the relatives (27%). There was also an increased frequency of hypertriglyceridemia (28% against expected 15%), mainly because of a high prevalence of HLP type IV (24%). On agarose gel electrophoresis a "late pre-beta" band, probably indicative of an increased amount of intermediary LP particles, was frequently present (47%) among relatives not classified as HLP type III. Type-III patients with hypertriglyceridemia were characterized by a significantly higher body weight than those with normotriglyceridemic type III. However, there was no qualitative difference in the composition of the lipoproteins in normotriglyceridemic and hypertriglyceridemic type-III patients. A genetic analysis of the LP patterns within the families showed several examples of vertical transmission of HLP type III. There was no sex linkage. Six of thirteen analyzed parents showed LP patterns classified as HLP type III. Another two parents were most probably carriers of the gene. Of the siblings to the probands, 23% showed a type-III pattern and another four (7%) showed LP patterns very similar to type III, fulfilling two of three criteria for HLP type III. The data support the concept that HLP type III is inherited as an autosomal dominant gene. It was indicated that HLP type IV with a late pre-beta band in VLDL may represent another expression of the gene for HLP type III. It is suggested that HLP type III may be a pathogenetically heterogenous group of lipid disorders. A separation of type III into two subgroups with low or normal and high LDL cholesterol concentration, respectively, may facilitate the understanding of the inheritance of type III as well as of the pathogenesis behind this LP abnormality.