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： 累积暴露于致动脉粥样硬化脂蛋白颗粒，以及携带的胆固醇质量， 是动脉粥样硬化的主要致病因素。因为它是累积暴露于 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超过 早期成年生命过程是动脉粥样硬化性心血管疾病（ASCVD）发展的中心。 迄今为止，脂蛋白颗粒数（LPN）的轨迹及其决定因素尚不清楚。有 已知有超过200种不同的单核苷酸多态性（SNP）与 胆固醇和甘油三酯水平。然而，总的来说，这些SNP只能解释12%的人群。 这些参数中的任何一个。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脂质浓度的影响，以及个体间 这些变量效应的变化表明基因表达的非序列依赖性变化， 例如，在一个实施例中，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， 可以作为一个早期的标志，脆弱性不利的生活方式因素方面的脂质稳态。我们 目的是探索不同的轨迹LPN在早期成人生活，环境和表观遗传 这些轨迹的介质，以及这些轨迹和ASCVD之间的关联。由于 对34年来的表观遗传、人体测量、饮食和其他生活方式模式进行了广泛的表型分析， 随访、系列血清样本可用性、亚临床动脉粥样硬化指标和ASCVD评估 事件，CARDIA研究提供了一个无与伦比的机会，了解多因素和复杂的 决定LPN相关ASCVD风险的因素。我们计划在纵向样品中测量LPN， CARDIA与NMR光谱，并描述了在LPN的轨迹在整个早期成人生活和他们的 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事件之间的关系。了解这些关键 LPN轨迹的介导物可能有助于临床医生针对脂质稳态不良的高风险个体 并确定未来治疗的分子靶点，以通过调节LPN降低ASCVD风险。

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.