A Longitudinal Epigenetic Study of Atherosclerosis

动脉粥样硬化的纵向表观遗传学研究

• 批准号: 9217955
• 负责人: YONGMEI LIU
• 金额: $ 149.77万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-12-15 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9217955
• 关键词: Age; Arterial Fatty Streak; Atherogenic Diet; Atherosclerosis; Bone Marrow; CD14 gene; Carotid Artery Plaques; Cells; Characteristics; Chronic; Clinical Data; Computer Simulation; Cross-Sectional Studies; DNA; Data; Data Set; Dissection; Enhancers; Epigenetic Process; Equation; Etiology; Funding; Gene Expression; Genetic; Genomic DNA; Genomics; Goals; Gray unit of radiation dose; Homeostasis; Image; Imaging Techniques; In Vitro; Individual; Inflammatory; Knock-out; Knockout Mice; Linear Regressions; Lipopolysaccharides; Measures; Mediating; Messenger RNA; Methods; Methylation; Modeling; Modification; Multi-Ethnic Study of Atherosclerosis; Muscle Development; Obesity; Outcome; Pathway interactions; Plant Roots; Play; Prospective Studies; Protocols documentation; Reaction; Reading; Risk; Risk Factors; Role; Running; SNP genotyping; Sampling; Scanning; Series; Smoking; Smooth Muscle; System; Therapeutic Intervention; Time; Transcription Coactivator; Transplantation; Ultrasonography; Validation; atherogenesis; base; cardiovascular disorder risk; causal model; disorder risk; epigenome; epigenomics; experimental study; follow-up; functional genomics; genomic data; in vivo; insight; lipid biosynthesis; lipid metabolism; monocyte; next generation; non-genetic; novel marker; targeted treatment; transcriptome; transcriptomics

Little is known about the epigenetic bases of atherosclerotic cardiovascular disease (CVD) risk. Our recent large cross-sectional study revealed many monocyte transcriptome and epigenome signatures associated with subclinical atherosclerosis. Some of these genomic features appeared to partially mediate the relationship between traditional CVD risk factors (e.g. age, obesity, and smoking) and measures of atherosclerosis. The transcriptome signatures included an H3K9me2 demethylase transcription coactivator, ARID5B, which is known to promote adipogenesis and smooth muscle development. Methylation of ARID5B enhancer was inversely associated with both ARID5B expression and atherosclerosis. Our experimental in vitro study further showed that ARID5B promotes expression of genes involved in atherosclerosis-related pro-inflammatory and lipid metabolism pathways after lipopolysaccharide (LPS) stimulation. These results support a pivotal epigenetic checkpoint for controlling immunometabolic homeostasis and promoting chronic inflammatory reactions, which may contribute to atherosclerosis. These data set a compelling stage for prospective studies of the candidate genomic features and mechanistic dissection of the role of ARID5B in atherogenesis. The goals of our proposed study are to identify atherosclerosis associated “promising” genomic features that are predictive of atherogenesis and its progression, to characterize their associations with plaque vulnerability, to determine their genetic and non-genetic predictors, and to elucidate their mechanistic linkage to atherogenesis. We will study 1,892 randomly selected subjects from four Multi-Ethnic Study of Atherosclerosis (MESA) field centers that have planned genomic, DNA methylomic, and transcriptomic data from purified CD14+ monocytes, as well as concurrent assessment of CVD risk factors and ultrasonographic carotid plaque burden from MESA Exam 5. We will repeat ultrasound imaging to quantify and characterize carotid plaques, and re-evaluate DNA methylomic and transcriptomic profiles of monocytes at MESA Exam 6, and we will perform in vivo and in vitro functional studies to achieve the following specific aims: Aim 1. To validate predictive effects of atherosclerosis-associated genomic features identified at Exam 5 on initiation and progression of atherosclerosis in a prospective study with 6-years of follow-up. Aim 2. To characterize the associations of the “promising” genomic features with carotid plaque vulnerability. Aim 3. To identify potential temporal and causal relationships between known genetic and non-genetic CVD risk factors, the “promising” genomic features, and plaque burden. Aim 4. To determine the functional consequences of alterations of most the “promising” genomic features. If successful, the identified “promising” genomic features will provide mechanistic insights into the etiology of atherosclerosis and potential targets for therapeutic intervention.

关于动脉粥样硬化心血管疾病（CVD）风险的表观遗传基础知之甚少。我们的最新消息 大型横断面研究表明，许多单核细胞转录组和表观基因组特征与 亚临床动脉粥样硬化。这些基因组特征中的一些似乎部分介导了关系 在传统的CVD危险因素（例如年龄，肥胖和吸烟）和动脉粥样硬化措施之间。这 转录组特征包括H3K9ME2脱甲基酶转录共激活因子ARID5B，即 已知可以促进脂肪形成和平滑肌发育。 ARID5B增强子的甲基化是 与ARID5B表达和动脉粥样硬化成反比。我们的实验性体外研究 表明ARID5B促进与动脉粥样硬化相关的促炎和 脂多糖（LPS）刺激后的脂质代谢途径。这些结果支持关键的表观遗传学 检查点用于控制免疫代谢稳态并促进慢性炎症反应，这 这些数据为候选人的前瞻性研究设定了令人信服的阶段 ARID5B在动脉粥样硬化中的作用的基因组特征和机理解剖。我们的目标 拟议的研究旨在确定与预测的“有前途的”基因组特征相关的动脉粥样硬化 动脉粥样硬化及其进展，以表征其与斑块脆弱性的关联，以确定 它们的遗传和非遗传预测因子，并阐明它们与动脉粥样硬化的机械联系。我们将 研究1,892位来自四个多种族动脉粥样硬化（MESA）野外中心的受试者 纯化的CD14+单核细胞也计划了基因组，DNA甲基甲基组和转录组数据 作为对MESA考试中CVD风险因素和超声颈椎斑块Burnen的同时评估 5。我们将重复超声成像以量化和表征颈动脉斑块，并重新评估DNA 单核细胞的甲基组和转录组学谱图在MESA检查6中，我们将在体内和体外进行 实现以下特定目的的功能研究：目标1。验证的预测效应 动脉粥样硬化相关的基因组特征在考试5鉴定出关于起始和进展的基因组特征 动脉粥样硬化在一项前瞻性研究中进行了6年的随访。目标2。表征 具有颈动脉斑块脆弱性的“有希望的”基因组特征。目标3。确定潜在的临时和因果 已知遗传和非遗传CVD风险因素，“有希望的”基因组特征以及 牌匾负担。目标4。确定大多数“有前途”的变化的功能后果 基因组特征。如果成功，确定的“有希望的”基因组特征将提供机械洞察力 进入动脉粥样硬化的病因和治疗干预的潜在靶标。