PATHOBIOLOGICAL DETERMINANTS OF ATHEROSCLEROSIS IN YOUTH

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The overall goal of the proposed research is to identify specific genes that mediate the pathogenesis of arterial lesions. The proposed research is part of a multicenter study to examine arterial lesions in 3000 young persons (15-34 years), and to identify risk factors that are associated with extent and nature of atherosclerotic lesions. This proposal is in response to recommendations of the review committee for phase I of the multicenter study to include genetic analyses (using restriction fragment length polymorphisms, RFLPs) that will detect associations between specific genes and atherogenesis. The long- term objectives of the multi-center study are: (1) to define more precisely the developmental processes by which arterial lesions characteristic of late childhood (fatty streaks) progress to form advanced lesions (fibrous plaques) associated with atherosclerosis in adulthood, and (2) to relate selected risk factors (serum cholesterol) and lipoprotein concentrations, cigarette smoking, blood pressure, diabetes, and obesity) to characteristics of atherosclerotic lesions in young persons. The aims of this proposed research relate to the second objective of the multi-center study and include: (1) determination of genotypes for each subject with respect to RFLPs in apolipoprotein and the LDL receptor genes (Southern blot analyses of DNA from liver samples sent from each collection center), (2) typing of subjects for apo E isoform genotypes using oligonucleotide probes, and (3) examination of the effects of RFLP genotypes on extent and characteristics of arterial lesions in young people. Detection of an associated RFLP not only provides evidence for genetic mediation of the pathogenesis of arterial lesions, but identifies which gene(s) is responsible for the underlying molecular processes of atherosclerosis. To maximize the probability of detecting RFLPs associated with pathogenesis of arterial lesions, specific RFLPS have been selected from published reports from other studies of human subjects. Most of these RFLPs have previously been associated with heart disease or altered levels of serum lipids and lipoproteins. This proposal presents a unique and important extension to genetic studies of heart disease, and will be the first direct examination of the effects of specific genes on the early stages of atherosclerotic lesions in young persons.