Epigenetic Determinants of Lipoproteins Across the Early Adult Life Course

项目摘要： 致动脉粥样硬化脂蛋白颗粒的累积暴露，以及携带的胆固醇质量 其中，是动脉粥样硬化的主要致病因素。因为它是累积的暴露于 介导动脉粥样硬化的致动脉粥样硬化脂蛋白颗粒，这些颗粒的变化模式 成人早期生活过程是动脉粥样硬化性心血管疾病(ASCVD)发展的中心环节。 到目前为止，脂蛋白颗粒数(LPN)及其决定因素的轨迹尚不清楚。确实有 已知与以下基因相关的200多个不同的单核苷酸多态性(SNP) 胆固醇和甘油三酯水平。然而，这些SNP总共只解释了12%的人口 这些参数中的任何一个的方差。饮食、体力活动和肥胖可以解释10-30%的差异 胆固醇。环境和遗传对血脂浓度以及个体间的影响 这些变量的影响的变化，表明非序列依赖的基因表达变化， 例如，表观遗传修饰，如DNA甲基化(DNaM)，可能在调节LPN和 血清胆固醇水平及其后果。如果dNaM介导了一些不利的LPN轨迹，它 可能是脂类平衡方面易受不良生活方式因素影响的早期标志。我们的 目的是探索LPN在成人早期生活、环境和表观遗传学中的不同轨迹 这些轨迹的中介者，以及这些轨迹与ASCVD之间的联系。由于 34年来对表观遗传学、人体测量学、饮食和其他生活方式的广泛表型 随访、系列血清样本可获得性、亚临床动脉粥样硬化措施和ASCVD评估 事件，CARDIA的研究提供了一个无与伦比的机会来理解多因素和复杂性 决定LPN相关ASCVD风险的因素。我们计划在纵向样本中测量LPN 并用核磁共振波谱描述成人早期生活中LPN的轨迹及其 相关的生活方式因素、人体测量特征和表观遗传修饰。我们还将量化 LPN与亚临床动脉粥样硬化和ASCVD事件的关系。了解这些关键 LPN轨迹的中介物可能有助于临床医生针对脂代谢不良的高危个体 并确定未来治疗的分子靶点，通过调节LPN来降低ASCVD风险。

Project Abstract: The cumulative exposure to atherogenic lipoprotein particles, as well as the cholesterol mass carried within them, are the primary causal factors for atherosclerosis. Since it is the cumulative exposure to atherogenic lipoprotein particles that mediates atherosclerosis, the patterns of change in these particles over the early adult life course are central to the development of atherosclerotic cardiovascular disease (ASCVD). To date, the trajectories of lipoprotein particle number (LPN) and their determinants are not known. There are greater than 200 distinct single nucleotide polymorphisms (SNPs) that are known to be associated with cholesterol and triglyceride levels. However, in aggregate these SNPs explain only 12% of the population variance in any of these parameters. Diet, physical activity, and obesity explain 10-30% of the variance in cholesterol. The environmental and genetic influence on lipid concentrations, as well as the inter-individual variation in the effects of these variables, suggest that non-sequence dependent changes in gene expression, e.g., epigenetic modifications like DNA methylation (DNAm), may play a significant role in modulating LPN and serum cholesterol levels and their consequences. If DNAm mediates some of the adverse LPN trajectories, it may serve as an early marker of vulnerability to adverse lifestyle factors in terms of lipid homeostasis. Our objective is to explore distinct trajectories of LPN across early adult life, the environmental and epigenetic mediators of these trajectories, and the associations between these trajectories and ASCVD. Due to the extensive phenotyping of epigenetic, anthropometric, and dietary and other lifestyle patterns across 34 years of follow-up, serial serum sample availability, subclinical atherosclerosis measures, and assessment of ASCVD events, the CARDIA study provides an unparalleled opportunity to understand the multifactorial and complex factors that determine LPN-associated ASCVD risk. We plan to measure LPN in longitudinal samples from CARDIA with NMR spectroscopy and describe the trajectories in LPN across early adult life and their associated lifestyle factors, anthropometric characteristics, and epigenetic modifications. We will also quantify the associations between LPN and subclinical atherosclerosis and ASCVD events. Understanding these key mediators of LPN trajectories may help clinicians target individuals at high risk for adverse lipid homeostasis and identify molecular targets for future therapies to reduce ASCVD risk through modulation of LPN.