INHERITANCE OF LOW-DENSITY-LIPOPROTEIN SUBCLASS PATTERNS IN FAMILIAL COMBINED HYPERLIPIDEMIA

The inheritance of low density lipoprotein (LDL) subclass patterns was investigated in 234 members of seven large kindreds with familial combined hyperlipidemia (FCHL), a disorder characterized by elevated LDL cholesterol and/or triglyceride and increased coronary disease risk in families. Analysis of LDL subclasses by nondenaturing gradient gel electrophoresis showed a predominance of large, buoyant LDL particles (pattern A) in 71% of the family members and a predominance of small, dense LDL particles (pattern B) in 29% of family members. Based on complex segregation analysis, pattern B appeared to be inherited as an autosomal trait with either a dominant or an additive mode of inheritance and a small, but significant, multifactorial inheritance component. The proposed allele for pattern B was common (frequency=0.3), and reduced penetrance was observed among men under age 20 and among women under age 50. These results in these FCHL families are consistent with those from a previously reported population-based sample of families, in which pattern B showed an apparent dominant mode of inheritance. In that study, reduced penetrance was observed for men under age 20 and for premenopausal women, but a somewhat lower allele frequency was found for pattern B (0.25). In the FCHL family members, LDL subclass pattern B was associated with significantly increased plasma levels of apolipoprotein B and triglyceride and decreased high density lipoprotein cholesterol. In comparison with a group of controls, the FCHL family members with pattern A had similar mean triglyceride levels, but higher mean apolipoprotein B. Thus, in families with FCHL, a predominance of small, dense LDL particles appears to be inherited as a common, single-gene trait, which is closely associated with the higher plasma triglyceride levels found in these families. The increased plasma apolipoprotein B levels found in FCHL cannot, however, be accounted for by this proposed locus.