PROJECT 2 - Lipoproteins, oxidataive damage, and responses to diet

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Lipid and lipoprotein phenotypes and markers of oxidative damage are among the strongest, most consistent predictors of cardiovascular disease (CVD). With a few notable exceptions, the genes that govern variation in these important risk factor phenotypes are poorly characterized, and it appears that there may be many novel genes involved which were not previously suspected. The overarching goal of this project is to search the genome for quantitative trait loci (QTLs) that influence markers of lipoprotein metabolism and oxidative damage, to locate and identify these genes, and ultimately to better understand the metabolic processes involved. The traits that we will assess include lipid and lipoprotein measures of LDLs and HDLs and plasma indicators of oxidative damage. In addition, we will focus on identifying the effects ofgenotype x environment interactions on these CVD traits, specifically, responses to changing levels of dietary components, such as fat, cholesterol, and the antioxidant vitamin E, and also age-related changes. Exploiting our existing resources (i.e., pedigreed baboons, statistical genetic tools, frozen samples from previous diet studies, and availability of genotypes for the microsatellite markers comprising the baboon linkage map) plus data from a new dietary challenge experiment, we propose the following specific aims: (1) to detect, map, and statistically characterize QTLs that affect lipid and lipoprotein phenotypes on different diets, (2) to determine the extent to which genes affect indicators of oxidative damage, (3) to determine the pleiotropic effects of genes that influence lipoprotein phenotypes and oxidative damage indicators, (4) to determine the effects of genes on long-term longitudinal changes in CVD risk factors (by means of re-challenging baboons that had previously undergone the dual dietary challenge experiment), and (5) to determine the effects of genes on responses of oxidative damage indicators to a high dose of vitamin E (by means of adding a new diet to the re-challenge protocol). Accomplishing these specific aims will enable us to detect, locate, and characterize genes that govern variation in well established CVD risk factors. Based on the close phylogenetic relationship of baboons and humans, the results from our studies will provide insights into the genes that underlie the onset and progression of atherosclerosis in humans.