Low density lipoprotein (LDL) heterogeneity : Implications for cardiovascular disease and genetic influence

Abstract: The low density lipoprotein (LDL) particle population is heterogeneous with regard to several structural and functional properties that may influence its atherogenic potential. A preponderance of small, dense LDL is associated with an increased risk of coronary heart disease (CHD), and also predicts future CHD events. However, the metabolic pathways for the formation of the small, dense LDL are not yet fully understood. There is strong evidence that the LDL particle size distribution is under genetic influence, although the major regulating genes remain unknown. The present studies were conducted to further elucidate the role of LDL heterogeneity in cardiovascular disease, and to evaluate the metabolic arid genetic determinants of LDL particle size distribution. In study I the influence of LDL particle size distribution on intima-media thickness (IMT) of the common carotid artery (CCA) was investigated in healthy 50-year-old men. A high-resolution nondenaturing polyacrylamide gradient (3-7.5%) gel electrophoresis (GGE) procedure was developed to measure LDL peak particle size (run), relative distribution (%) and plasma concentration (mg/L) of four LDL subfractions. The IMT of the CCA was measured by B-mode ultrasound. The results of this study show that the plasma concentration of small, dense LDL (LDL-III) is a strong and independent indicator of early atherosclerosis in healthy, middleaged men. In study II the effects of artificial and exhaustive lipolysis on potentially atherogenic properties of LDL were investigated in healthy normotriglyceridaemic men. After in vitro and in vivo lipolysis of serum and plasma triglycerides, respectively, the LDL particle population was characterised with regard to size, composition, and susceptibility to oxidative modification The results of this study demonstrate that an exaggerated or efficient lipolysis of plasma triglycerides results in the generation of new LDL particles with an increased content of alpha-tocopherol and increased resistance to oxidative modification. In studies III-V the influence of common functional variants in candidate genes (encoding proteins or enzymes with important roles in lipoprotein metabolism) on LDL heterogeneity was investigated. In study III, polymorphisms in the cholesteryl ester transfer protein (CETP), lipoprotein lipase (LPL), hepatic lipase (HL), and apolipoprotein E (apoE) genes were studied in relation to LDL particle size in 377 healthy, middle-aged men The results of this study show that the investigated polymorphisms are associated with moderate effects on the LDL particle size, consistent with respect to protein function and proposed association with CHD risk. In study IV, the isolated and combined effects of the apolipoprotein. B (apoB) and the apoE polymorphisms on LDL particle size and risk of CHD were investigated in 405 survivors of a first myocardial infarction before the age of 60, and 769 healthy individuals. The results of this study demonstrate that a genegene interaction between the apoB and apoE polymorphisms is associated with a markedly elevated concentration of small, dense LDL, which is further conveyed to an increased risk of myocardial infarction. In study V, the influence of a common variant in the MTP gene promoter on the secretion pattern of apoBcontaining lipoproteins and plasma LDL heterogeneity was investigate& A total of 12 healthy men were recruited by genotype to participate in apoB stable isotope turnover studies, and kinetic parameters were calculated by multicompartmental modelling. LDL particle size was measured in 377 healthy, middle-aged men The results of this study show that the MT? promoter polymorphism is associated with a reduced direct production of IDL+LDL particles, which appears to be directly related to lower plasma concentrations of large LDL particles. Conclusions: The studies presented here demonstrate that the atherogenic properties of plasma LDL goes far beyond the routinely measured LDL cholesterol concentration. LDL heterogeneity appears to be regulated by complex metabolic pathways, which are further modulated by common genetic variability.