Low density lipoprotein (LDL) cholesterol is a major risk factor for coronary heart disease (CHD), and the clustering of CHD in families may be related to the familial aggregation of lipoprotein levels. Heterogeneity within the major lipoprotein classes has also been recognized for many years. We have hypothesized that subclasses within the LDL range of particles, which have been defined and measured in our laboratory, reflect genetic influences on lipoprotein metabolism. Our preliminary results support this genetic hypothesis and indicate that a predominance of small, dense LDL particles is a risk factor for coronary heart disease. We propose to perform genetic studies of low density lipoprotein subclasses in 160 families in which the proband (index case) has metabolically defined hypercholesterolemia. The probands will be identified by Dr. Scott Grundy at the University of Texas at Dallas. Dr. Grundy will perform turnover studies of the probands, under separate funding, to characterize them metabolically as having hypercholesterolemia due to overproduction of LDL or due to LDL clearances defects. For the present study, all first-degree relatives of these probands (parents, siblings, children, and spouse) will be recruited. Blood samples will be obtained from these relatives for LDL subclass analysis and for lipid and apoprotein determinations. In addition, an interview will be conducted to obtain information on behavioral and environmental risk factors such as smoking, exercise, and diet. This data will be used to determine whether LDL subclasses are genetically controlled in families with hypercholesterolemia. We will investigate the relationships between the LDL subclass phenotype characterized by a predominance of small, dense LDL and both overproduction of apoprotein B and LDL clearance defects in family members. In addition, we will determine whether an """"""""age-of-onset"""""""" effect exists for the expression of the LDL subclass phenotypes, and whether genetic-environmental interactions can be detected. The results of this study will elucidate the role of LDL subclasses in metabolically defined hypercholesterolemia, and whether genetic control of LDL subclasses contributes to the familial aggregations of these disorders.
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