Epigenetic Determinants of Lipoproteins Across the Early Adult Life Course

成人早期生命过程中脂蛋白的表观遗传决定因素

• 批准号: 10570262
• 负责人: John Thomas Wilkins
• 金额: $ 42.95万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10570262
• 关键词: Address; Adult; Age; Atherosclerosis; Behavioral; Biochemical Pathway; Candidate Disease Gene; Carbohydrates; Characteristics; Cholesterol; Complex; Coronary Artery Risk Development in Young Adults Study; DNA Methylation; Data; Development; Diet; Environment; Environmental Risk Factor; Epigenetic Process; Event; Exposure to; Future; Gene Expression; Genes; Genetic; Genetic Variation; Genotype; High Density Lipoprotein Cholesterol; Homeostasis; Individual; Life; Life Cycle Stages; Life Style; Link; Lipids; Lipoproteins; Measurement; Measures; Mediating; Mediation; Mediator; Mendelian randomization; Methylation; Modification; Molecular; Molecular Target; Myocardial Infarction; NMR Spectroscopy; National Heart, Lung, and Blood Institute; Obesity; Participant; Pathway interactions; Pattern; Phenotype; Physical activity; Play; Population; Recommendation; Residual state; Risk; Risk Factors; Role; Sampling; Serum; Single Nucleotide Polymorphism; Strategic vision; Stroke; Time; Triglycerides; Virulence Factors; burden of illness; cardiovascular disorder risk; clinically significant; dietary; disorder risk; emerging adult; epigenome-wide association studies; follow-up; high risk; inter-individual variation; lifestyle factors; lipoprotein cholesterol; methylation pattern; middle age; particle; personalized approach; phenotypic data; prevent; young adult

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.

项目摘要： 累积暴露于动脉粥样硬化脂蛋白颗粒以及携带的胆固醇质量 在其中，是动脉粥样硬化的主要因素。因为这是累积暴露 介导动脉粥样硬化的动脉粥样硬化脂蛋白颗粒，这些颗粒的变化模式 成人早期生活课程对于动脉粥样硬化心血管疾病（ASCVD）的发展至关重要。 迄今为止，尚不清楚脂蛋白颗粒数（LPN）及其决定因素的轨迹。有 大于200种不同的单核苷酸多态性（SNP），已知与 胆固醇和甘油三酸酯水平。但是，在总体中，这些SNP仅解释了人口的12％ 这些参数中的任何一个方差。饮食，体育锻炼和肥胖解释了10-30％的差异 胆固醇。环境和遗传对脂质浓度的影响以及个体间 这些变量的影响的变化表明，基因表达的非序列依赖性变化， 例如，诸如DNA甲基化（DNAM）之类的表观遗传修饰可能在调节LPN和 血清胆固醇水平及其后果。如果Dnam介导了一些不良LPN轨迹，则 就脂质稳态而言，可能是对不利生活方式因素的脆弱性的早期标志。我们的 目标是在成年早期，环境和表观遗传的早期探索LPN的不同轨迹 这些轨迹的介体以及这些轨迹与ASCVD之间的关联。由于 在34年的表观遗传，人体测量学以及饮食和其他生活方式模式的广泛表型 随访，串行血清样品可用性，亚临床动脉粥样硬化措施和ASCVD评估 事件，Cardia研究提供了一个无与伦比的机会，可以理解多因素和复杂 决定LPN相关的ASCVD风险的因素。我们计划在纵向样品中测量LPN 带有NMR光谱的Cardia，描述了成年早期LPN中LPN的轨迹及其轨迹 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与ASCVD事件之间的关联。了解这些关键 LPN轨迹的介体可以帮助临床医生针对不良脂质稳态的高风险的人 并确定通过调节LPN降低ASCVD风险的未来疗法的分子靶标。

项目成果

Analysis of apoB Concentrations Across Early Adulthood and Predictors for Rates of Change Using CARDIA Study Data.

• DOI: 10.1016/j.jlr.2022.100299
• 发表时间: 2022-12
• 期刊: JOURNAL OF LIPID RESEARCH
• 影响因子: 6.5
• 作者: Wilkins, John T.;Ning, Hongyan;Sniderman, Allan;Stone, Neil;Otvos, James;Jacobs, David R.;Shah, Ravi;Murthy, Venkatesh L.;Rana, Jamal;Allen, Norrina;Lloyd-Jones, Donald M.
• 通讯作者: Lloyd-Jones, Donald M.