Abstract
Small, dense LDL particles have been associated with an increased risk of coronary artery disease, and cholesteryl ester transfer protein (CETP) has been suggested to play a role in LDL particle remodeling. We examined the relationship between LDL heterogeneity and plasma CETP mass in familial hypercholesterolemia (FH). LDL particles were characterized by polyacrylamide gradient gel electrophoresis in a total of 259 FH heterozygotes and 208 nonFH controls. CETP mass was measured by enzyme-linked immunosorbent assay in a subgroup of 240 participants, which included 120 FH patients matched with 120 controls. As compared with controls, FH subjects had an 11% higher CETP mass. Moreover, LDL-peak particle diameter (LDL-PPD) was significantly smaller in FH heterozygotes than in controls (258.1 +/- 4.8 vs. 259.2 +/- 4.1 A; P = 0.01) after adjustment for covariates. There was also an inverse relationship between LDL-PPD and CETP mass (R = -0.15; P = 0.02), and this relationship was abolished by adjustment for the FH/control status, indicating that LDL-PPD changes in FH are mediated, at least in part, by an increase in plasma CETP mass concentrations. These results suggest that increased plasma CETP mass concentrations could lead to significant LDL particle remodeling in FH heterozygotes and could contribute to the pathogenesis of atherosclerosis.
Highlights
Small, dense LDL particles have been associated with an increased risk of coronary artery disease, and cholesteryl ester transfer protein (CETP) has been suggested to play a role in LDL particle remodeling
To the best of our knowledge, this was the first study to examine the role of CETP as the determinant of LDL size heterogeneity in a large cohort of familial hypercholesterolemia (FH) heterozygotes and controls
Our results suggested that LDL receptor (LDLR) gene mutations leading to FH are associated with significant variations in electrophoretic characteristics of LDL particle size; FH heterozygotes having smaller LDL-peak particle diameter (LDL-PPD) associated with an accumulation of mid-size LDL particles (255–260 Å)
Summary
Dense LDL particles have been associated with an increased risk of coronary artery disease, and cholesteryl ester transfer protein (CETP) has been suggested to play a role in LDL particle remodeling. We examined the relationship between LDL heterogeneity and plasma CETP mass in familial hypercholesterolemia (FH). As characterization of Abbreviations: apoE3, apolipoprotein E3; BMI, body mass index; CAD, coronary artery disease; CETP, cholesteryl ester transfer protein; FH, familial hypercholesterolemia; LDL-C, LDL cholesterol; LDL-PPD, LDL-peak particle diameter; LDLR, LDL receptor. LDL size could be relevant for the understanding of the variability in CAD risk among FH patients, the objective of the present study was to examine LDL size heterogeneity and its relationship to CETP in a large cohort of genetically-defined FH heterozygotes and controls
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