Inheritance of low-density lipoprotein subclass patterns: results of complex segregation analysis

Heterogeneity in the size of low-density lipoprotein (LDL) particles was used to identify two distinct patterns based on gradient gel electrophoresis analysis. These two phenotypes, LDL subclass pattern A and pattern B, were characterized by a predominance of large, buoyant LDL particles and small, dense LDL particles, respectively. The inheritance of these LDL subclass patterns was investigated in a sample of 61 healthy families including 301 individuals. LDL subclass pattern B was present in 31% of the subjects, with the prevalence varying by gender, age, and (in women) menopausal status. Complex segregation analysis suggested a major locus controlling LDL subclass patterns. The model providing the best fit to the data included a dominant mode of inheritance with a frequency of .25 for the allele determining LDL subclass pattern B and reduced penetrance for men under age 20 and for premenopausal women. Thus, the allele for the LDL subclass pattern characterized by a predominance of small, dense LDL particles appears to be very common in the population, although not usually expressed until adulthood in men and until after menopause in women. The presence of a major gene controlling LDL subclass could explain much of the familial aggregation of lipid and apolipoprotein levels and may be involved in increased risk of coronary heart disease.