Atherosclerosis susceptibility is a function of both environmental, principally dietary, influences and genetic constitution. Although perhaps 5-10% of the population are genetically resistant and another 5-10% susceptible to atherosclerosis, in the vast majority of the population, disease is a function of environment-gene interactions. In this research proposal, we intend to utilize our expertise in biochemistry and molecular biology and the resouces of the Rockefeller University Hospital Clinical Research Center to define and ultimately to understand the range of human variation in response to diet. Four projects are proposed: 1. Apolipoprotein Gene RFLPs, Lipoprotein Abnormalities and Atherosclerosis Susceptibility. To perform association and linkage studies to infer a role for the apolipoprotein gene loci in lipoprotein abnormalities and myocardial infarction susceptibility. Putative abnormal alleles will be cloned and studied functionally and structrally for causative mutations. 2. Dietary and Genetic Determinants of LDL Cholesterol Levels. To define the range of interindividual responsiveness of LDL cholesterol levels to dietary cholesterol and saturated fat in normal volunteers and patients. To explore the basis for dietary responsiveness with physiological, biochemical and genetic studies. 3. Regulation of Postprandial Lipoprotein Metabolism. To better understand the regulation of chylomicron and chylomicron remnant clearance by studying patients and normal volunteers using the vitamin A-fat tolerance test. The effects of diet and exercise will be studied in normal volunteers as well as drug effects in patients. To define whether delayed chylomicron clearance is due to defects in the particle or in lipoprotein lipase. 4. Dietary and Genetic Determinants of HDL Cholesterol Levels. To recruit individuals with primary increases or decreases in HDL cholesterol levels and determine, by in vivo turnover studies, if the abnormality is in synthesis or catabolism. To study the effects of dietary fat on HDL levels and turnover parameters. To determine the genetic basis underlying individual differences. These studies should provide insights into understanding gene-diet interactions underlying atherosclerosis susceptibility. They will also significantly contribute to the emerging new field of nutritional genetics.
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