A Longitudinal Epigenetic Study of Atherosclerosis

关于动脉粥样硬化性心血管疾病（CVD）风险的表观遗传基础知之甚少。我们最近 大的横断面研究揭示了许多单核细胞转录组和表观基因组特征， 亚临床动脉粥样硬化其中一些基因组特征似乎部分介导了这种关系 传统的CVD危险因素（如年龄、肥胖和吸烟）与动脉粥样硬化指标之间的关系。的 转录组特征包括H3K9me2脱甲基酶转录辅激活因子ARID5B， 已知促进脂肪生成和平滑肌发育。ARID5B增强子的甲基化是 与ARID5B表达和动脉粥样硬化呈负相关。我们的体外实验研究进一步 显示ARID5B促进参与动脉粥样硬化相关的促炎基因的表达， 脂多糖（LPS）刺激后的脂质代谢途径。这些结果支持了一个关键的表观遗传学 用于控制免疫代谢稳态和促进慢性炎症反应的检查点， 可能导致动脉粥样硬化。这些数据为候选人的前瞻性研究提供了一个引人注目的阶段 基因组特征和ARID5B在动脉粥样硬化形成中的作用的机制解剖。我们的目标 提出的研究是确定动脉粥样硬化相关的“有希望的”基因组特征，这些特征预测动脉粥样硬化的发生。 动脉粥样硬化形成及其进展，以表征其与斑块易损性的关联，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形成的机制联系。我们将 从4个多种族动脉粥样硬化研究（梅萨）现场中心随机选择1，892名受试者 已经计划了来自纯化的CD14+单核细胞的基因组、DNA甲基化组和转录组数据， 同时评估CVD风险因素和梅萨检查的超声颈动脉斑块负荷 5.我们将重复超声成像，以量化和描述颈动脉斑块，并重新评估DNA 在梅萨考试6单核细胞的甲基化和转录组学概况，我们将在体内和体外进行 功能研究，以实现以下具体目标：目标1。为了验证预测效果， 在第5次检查中发现的动脉粥样硬化相关基因组特征， 动脉粥样硬化的前瞻性研究，随访6年。目标2.为了描述 “有前途的”基因组特征与颈动脉斑块的脆弱性。目标3。为了确定潜在的时间和因果关系 已知的遗传和非遗传CVD风险因素之间的关系，“有希望的”基因组特征， 牙菌斑负担目标4。为了确定大多数“有希望的”改变的功能后果， 基因组特征如果成功的话，所识别的“有希望的”基因组特征将提供机制性的见解。 动脉粥样硬化的病因学和治疗干预的潜在靶点。

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.