Epigenomic and Metabolomics Determinants of Subclinical and Clinical Vascular and Myocardial Disease

亚临床和临床血管和心肌疾病的表观基因组学和代谢组学决定因素

• 批准号: 10622473
• 负责人: Yan Sun
• 金额: $ 37.46万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-15 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10622473
• 关键词: 20 year old; Age; Algorithms; Asia; Atherosclerosis; Biological Process; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular system; Caring; Carotid Artery Plaques; Cessation of life; Clinical; Collection; Complex; Coronary Arteriosclerosis; Detection; Development; Diabetes Mellitus; Disease; Disease Management; Disease Outcome; Dyslipidemias; EFRAC; Echocardiography; Environment; Environmental Exposure; Environmental Risk Factor; Epigenetic Process; Evaluation; Feasibility Studies; Functional disorder; Funding; Gene Expression; Genes; Genetic; Genetic Variation; Genomics; Goals; Heart failure; High Density Lipoprotein Cholesterol; High Prevalence; Hypertriglyceridemia; India; Individual; Investigation; Ischemia; Joints; Lead; Left; Link; Low Prevalence; Measurement; Measures; Mediating; Mendelian randomization; Methods; Modification; Molecular; Myocardial Infarction; National Heart, Lung, and Blood Institute; Natural History; Obesity; Participant; Pathway interactions; Phenotype; Physiological; Play; Population; Population Study; Prevention; Program Research Project Grants; Risk; Risk Assessment; Risk Factors; Risk Reduction; Role; Sampling; South Asian; Technology; Testing; Time; Vascular Diseases; Ventricular; Visit; acquired factor; ambient air pollution; arterial stiffness; cardiometabolic risk; cardiovascular disorder prevention; cardiovascular disorder risk; cardiovascular health; carotid intima-media thickness; clinical phenotype; cohort; coronary calcium scoring; design; disease phenotype; disorder risk; epigenome; epigenomics; follow-up; genetic risk factor; genome wide association study; genomic locus; human disease; improved; inter-individual variation; machine learning algorithm; metabolome; metabolomics; multiple omics; novel; personalized diagnostics; population based; precision medicine; predictive marker; predictive modeling; preservation; response; risk prediction; small molecule; synergism

PROJECT SUMMARY / ABSTRACT: Project 3 To transform conventional imprecise cardiovascular disease (CVD) risk assessments towards more precise risk prediction and early-stage detection, Project 3 will conduct an untargeted multi-omic study to investigate molecular factors associated with subclinical and clinical CVD phenotypes along atherosclerotic CVD (ASCVD) and heart failure (HF) pathways including HF with preserved (HFpEF) and reduced ejection fraction (HFrEF). Both genetic and environmental risk factors contribute to the development of CVD. Identified genetic variations only account for a small proportion of ASCVD and HF risk in the population. Effect of environmental contributions to CVD, however, remain largely unexplored at the molecular level. Biomolecules, such as epigenetic and metabolomic markers, can capture complementary molecular effectors in response to environmental exposures, and alter biological functions at multiple levels. Therefore, studying multiple molecular layers (e.g., epigenome and metabolome) may help discover novel pathways and mechanisms through which environmental exposures influence CVD development and provide new targets for prevention and management of CVD. This is particularly important for populations, such as South Asians, who suffer a high burden of CVD at young ages and have unique cardiometabolic risk profile (e.g., very high prevalence of diabetes and dyslipidemia despite relatively low prevalence of obesity), but are underrepresented in current population studies of epigenomics, metabolomics and genomics. Examining the changes in multi-omic markers in relation to the natural history of CVD phenotypes within the same individuals provides a controlled and unbiased evaluation of these relationships. To identify epigenomic and metabolomic factors associated with subclinical (Aim 1, atherosclerosis and left ventricular systolic/diastolic dysfunction) and clinical CVD (Aim 2, coronary artery disease, HFpEF, ischemic and non-ischemic HFrEF), we will conduct epigenome-wide and metabolome-wide association analyses of 3,000 participants informatively selected from the Precision Cardiovascular Phenotyping and Pathophysiological Pathways in the CARRS cohort (Precision-CARRS), measured at baseline and the first follow-up visit, and replicate the findings in external cohorts. To determine the joint impact of genomic, epigenomic and metabolomic profiles on subclinical and clinical CVD and build prediction models (Aim 3), we will apply advanced multi-omic approaches, machine learning algorithms and causal inference methods. Lastly, we will assess whether epigenomic and metabolomic profiles are associated with, and mediate ambient air pollution (from Project 2) in relation to subclinical and clinical CVD (Aim 4). Through comprehensive multi-omic measurements and integrative analyses, Project 3 will improve the risk assessment, molecular understanding and precision medicine of CVD in South Asians.

项目总结/摘要：项目3 将传统的不精确的心血管疾病（CVD）风险评估转变为更精确的风险评估。 风险预测和早期检测，项目3将进行非靶向多组学研究， 与沿着动脉粥样硬化性CVD（ASCVD）的亚临床和临床CVD表型相关的分子因素 和心力衰竭（HF）途径，包括射血分数保留（HFpEF）和射血分数降低（HFrEF）的HF。 遗传和环境风险因素都有助于CVD的发展。已鉴别基因变异 仅占人群中ASCVD和HF风险的一小部分。环境影响 然而，对CVD的贡献在分子水平上仍然很大程度上未被探索。生物分子如 表观遗传和代谢组学标记，可以捕获互补的分子效应器， 环境暴露，并在多个层面上改变生物功能。因此，研究多重 分子层（例如，表观基因组和代谢组）可能有助于发现新的途径和机制 环境暴露通过这些途径影响CVD的发展，并提供新的预防目标 CVD的管理。这对南亚人等人口尤为重要，他们遭受着 年轻时CVD负担高，具有独特的心脏代谢风险特征（例如，极高发病率的 糖尿病和血脂异常，尽管肥胖的患病率相对较低），但在目前的 表观基因组学、代谢组学和基因组学的人口研究。检查多组学标记的变化 与同一个体内CVD表型的自然史相关，提供了一个受控且 对这些关系的客观评价。为了确定表观基因组学和代谢组学因素与 亚临床（目的1，动脉粥样硬化和左心室收缩/舒张功能障碍）和临床CVD（目的2， 冠状动脉疾病，HFpEF，缺血性和非缺血性HFrEF），我们将进行表观基因组范围和 对从Precision中信息性选择的3，000名参与者进行全代谢组关联分析 CARRS队列中的心血管表型和病理生理学途径（Precision-CARRS）， 在基线和第一次随访时测量，并在外部队列中复制结果。以确定 基因组学、表观基因组学和代谢组学特征对亚临床和临床CVD和建筑物联合影响 预测模型（目标3），我们将应用先进的多组学方法，机器学习算法和 因果推理方法。最后，我们将评估表观基因组学和代谢组学特征是否与 与亚临床和临床CVD（目标4）相关的环境空气污染（来自项目2）。 项目3通过综合的多经济措施和综合分析， 评估、分子理解和精确医学在南亚人的心血管疾病。