GENETIC DETERMINANTS OF PLASMA LIPOPROTEINS

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Hepatic lipase is a 476 amino acid glycoprotein that catalyzes phospholipid and triglyceride hydrolysis in circulating lipoproteins. Hepatic lipase activity varies widely among individuals, and this variation has been associated with inter-individual differences in the plasma concentrations of high density lipoproteins (HDL), particularly the HDL2 subfraction, the rates of low density lipoprotein (LDL) synthesis and catabolism, and in the size distribution of LDL. Preliminary data from our laboratory suggest that ethnic differences in hepatic lipase activity may also be responsible for the well known differences in plasma HDL concentrations between African American and white American men. Since these studies are based on correlations between phenotypes, however, they are subject to confounding by secondary factors such as obesity and plasma triglyceride concentrations that may have independent effects on hepatic lipase activity and lipoprotein metabolism. Therefore it is difficult to infer from these studies whether or not the relationship between hepatic lipase activity and plasma lipoprotein concentrations is causal. Thus a key question that remains unanswered by these studies is "does primary variation in hepatic lipase activity cause variation in plasma lipoprotein metabolism in humans?" A second question that remains unanswered is what causes the wide variation in hepatic lipase activity observed in otherwise healthy individuals? These two questions provide the focus of this competing continuation. In the first two Specific Aims, we will compare individuals with genetically defined hepatic lipase activities to determine: i) whether genetic variation in hepatic lipase activity accounts for the well known differences in plasma HDL-C concentrations between African American and white men, and ii) whether primary differences in hepatic lipase activity cause differences in plasma lipoproteins. In the third Specific Aim, we will determine whether genetic polymoprhism in hepatic lipase contributes to the very high hepatic lipase activities commonly seen in white Men. These studies will help to determine the role of variation in hepatic lipase activity in determining plasma HDL concentrations, and LDL size distribution, two important risk factors for coronary artery disease.