Lipoproteins, oxidataive damage, and responses to diet

脂质和脂蛋白表型以及氧化损伤的标志物是心血管疾病(CVD)最强、最一致的预测指标之一。除了少数值得注意的例外，控制这些重要风险因素表型变异的基因特征不佳，似乎涉及到许多以前没有怀疑的新基因。这个项目的首要目标是搜索基因组中影响脂蛋白代谢和氧化损伤标记物的数量性状基因座(QTL)，以定位 并确定这些基因，最终更好地了解涉及的代谢过程。我们将评估的特征包括低密度脂蛋白和高密度脂蛋白的脂和脂蛋白测量以及血浆氧化损伤指标。此外，我们将重点确定基因x环境交互作用对这些心血管疾病特征的影响，特别是对不断变化的饮食成分水平的反应，如脂肪、胆固醇和抗氧化剂维生素E，以及与年龄相关的变化。利用我们现有的资源(例如，纯种狒狒、统计数据 遗传工具、以前饮食研究中的冰冻样本以及构成狒狒连锁图谱的微卫星标记的基因类型的可用性)加上一项新的饮食挑战实验的数据，我们提出了以下具体目标：(1)检测、定位并统计表征不同饮食中影响脂质和脂蛋白表型的QTL；(2)确定基因影响氧化损伤指标的程度；(3)确定影响脂蛋白表型和氧化损伤的基因的多效性效应 (4)确定基因对心血管疾病风险因素长期纵向变化的影响(通过重新挑战先前进行过双重饮食挑战实验的狒狒)，以及(5)确定基因对氧化损伤指标对高剂量维生素E反应的影响(通过在重新挑战方案中添加新的饮食)。实现这些特定的目标将使我们能够检测、定位和表征控制已确立的心血管疾病风险因素中的变异的基因。根据收盘价 我们的研究结果将为我们深入了解导致人类动脉粥样硬化发生和发展的基因提供帮助。

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.