A Longitudinal Epigenetic Study of Atherosclerosis

动脉粥样硬化性心血管疾病(CVD)风险的表观遗传学基础知之甚少。我们最近 大型横断面研究显示，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地调节了这种关系 传统的心血管疾病危险因素(如年龄、肥胖和吸烟)和动脉粥样硬化的测量之间的关系。这个 转录组签名包括H3K9me2去甲基酶转录共激活子ARID5B，它是 已知可促进脂肪生成和平滑肌肉发育。ARID5B增强子甲基化 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促进与动脉粥样硬化相关的促炎和 脂多糖刺激后的脂代谢途径。这些结果支持一个关键的表观遗传学 控制免疫代谢动态平衡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奠定了令人信服的基础 ARID5B在动脉粥样硬化形成中作用的基因组特征和机制剖析。我们的目标是 建议的研究是确定与动脉粥样硬化相关的、可以预测 动脉粥样硬化的发生及其进展，以表征其与斑块易损性的关系，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。我们会 从动脉粥样硬化(MESA)领域中心的四个多种族研究中随机挑选1,892名受试者进行研究 也计划了来自纯化的CD14+单核细胞的基因组、DNA甲基组和转录数据 MESA检查同时评估心血管疾病危险因素和颈动脉斑块负荷 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 MESA考试6中单核细胞的甲基化组和转录图谱，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.验证预测效果 动脉粥样硬化相关基因组特征在试验5中确定的启动和进展 一项前瞻性研究中的动脉粥样硬化，随访6年。目标2.描述不同文化之间的联系 具有颈动脉斑块脆弱性的“有希望的”基因组特征。目标3.确定潜在的时间性和因果关系 已知的遗传性和非遗传性心血管疾病危险因素之间的关系、“有希望的”基因组特征以及 斑块负担。目标4.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，识别出的“有希望的”基因组特征将提供机械性的洞察 研究动脉粥样硬化的病因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.