Contribution of the hepatic lipase gene to the atherogenic lipoprotein phenotype in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCH) is a common genetic lipid disorder w ith a frequency of 1-2% in the population. In addition to the hypercholeste rolemia and/or hypertriglyceridemia that affected individuals exhibit, smal l, dense LDL particles and decreased HDL, cholesterol levels are traits fre quently associated with FCH, Recently, we reported that families with FCH a nd families enriched for coronary artery disease (CAD) share genetic determ inants for the atherogenic lipoprotein phenotype (ALP), a profile presentin g with small, dense LDL particles, decreased HDL-cholesterol levels, and in creased triglyceride levels. Other studies in normolipidemic populations ha ve shown that the hepatic lipase (HL) gene is linked to HDL-cholesterol lev els and that a polymorphism within the HL promoter (-514C-->T) is associate d with increased HDL-cholesterol levels as well as larger, more buoyant LDL particles. In the present study, we tested whether the HL gene locus also contributes to ALP in a series of Dutch FCH families using nonparametric si bpair linkage analysis and association analysis. Evidence for linkage of LD L particle size (P < 0.019), HDL-cholesterol (P < 0.003), and triglyceride levels (P < 0.026) to the HL gene locus was observed. A genome scan in a su bset of these families exhibited evidence for linkage of PPD (LOD = 2.2) an d HDL-cholesterol levels (LOD = 1.2) to the HL gene locus as well. The -514 C-->T promoter polymorphism was significantly associated (P < 0.0001) with higher HDL-cholesterol levels in the unrelated males of this population, bu t not in unrelated females. No association was observed between the polymor phism and LDL particle size or triglyceride levels. jlr Our results provide support that ALP is a multigenic trait and suggest that the relationship b etween small, dense LDL particles, HDL cholesterol, and triglyceride levels in FCH families is due, in part, to common genetic factors.