INHERITED SUSCEPTIBILITY DETERMINES THE DISTRIBUTION OF DENSE LOW-DENSITY-LIPOPROTEIN SUBFRACTION PROFILES IN FAMILIAL COMBINED HYPERLIPIDEMIA

Familial combined hyperlipidemia (FCH) is a heritable lipid disorder, in which dense low-density lipoprotein (LDL) subfraction profiles due to a predominance of small dense LDL particles are frequently observed . These small dense LDL particles are associated with cardiovascular d isease. Using segregation analysis, we investigated to what extent the se LDL subfraction profiles are genetically determined; also, the mode of inheritance was studied. Individual LDL subfraction profiles were determined by density gradient ultracentrifugation in 623 individuals of 40 well-defined Dutch FCH families. The individual LDL subfraction profile was defined as a quantitative trait by the continuous variable K, a reliable estimate of the relative contribution of each LDL subfr action to the overall profile. Variation in parameter K due to age, se x, and hormonal status was taken into account by introducing liability classes. Segregation analysis was performed by fitting a series of cl ass D regressive models, implemented in the Statistical Analysis for G enetic Epidemiology (SAGE) program, after which genetic models were co mpared using log-likelihood ratio tests. Our data show that 60% of the variability of parameter K could be explained by lipid and lipoprotei n levels and that a major autosomal locus, recessively inherited, with a population frequency of .42 +/- .07, and an additional polygenic co mponent of .25 best explained the clustering of atherogenic dense LDL subfraction profiles in these FCH families. Therefore, dense LDL subfr action profiles, associated with elevated lipid levels, appear to have a genetic basis in FCH.