Genetic Architecture of Cardiac Structure and Function and Its Impact on Heart Failure

心脏结构和功能的遗传结构及其对心力衰竭的影响

• 批准号: 10672986
• 负责人: Vasan S Ramachandran
• 金额: $ 71.05万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10672986
• 关键词: Affect; African American population; African ancestry; Age; Aging; Architecture; Atherosclerosis Risk in Communities; Biological; Cardiac; Cohort Analysis; Communities; Coronary Artery Risk Development in Young Adults Study; Data; Development; Drug Targeting; EFRAC; EchoGen; Echocardiography; Elderly; Ethnic Population; European ancestry; Event; Framingham Heart Study; Future; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Genetic Risk; Genomics; Heart; Heart Abnormalities; Heart failure; Heritability; Hispanic Community Health Study/Study of Latinos; Hispanic ancestry; Impairment; Incidence; Investigation; Jackson Heart Study; Left Atrial Function; Left Ventricular Remodeling; Life Cycle Stages; Machine Learning; Measures; Mediating; Mendelian randomization; Minority; Mitochondrial DNA; Modeling; Morbidity - disease rate; Multi-Ethnic Study of Atherosclerosis; Multiomic Data; Myocardial dysfunction; Pathogenesis; Pathway interactions; Phenotype; Physiology; Prevention; Proteins; Proteomics; Research; Right Ventricular Function; Risk; Risk Factors; Sampling; Structure; Trans-Omics for Precision Medicine; Underrepresented Populations; Variant; Veterans; adjudication; biobank; cardiovascular health; cohort; drug development; druggable target; efficacious treatment; genetic architecture; genetic association; genetic variant; genome sequencing; genome wide association study; genomic epidemiology; heart function; improved; inherited cardiomyopathy; insight; inter-individual variation; lifetime risk; machine learning algorithm; metabolomics; mortality; multi-ethnic; novel; novel strategies; personalized intervention; phenotypic data; polygenic risk score; population based; preservation; prevent; programs; prospective; risk prediction; sex; trait; whole genome

Heart failure (HF) increases with age markedly and is associated with a 50% 5-year mortality. Abnormalities of cardiac structure and impairment of cardiac function precede the development of HF and underlie HF subtypes. Cardiac structure and function are heritable - genome-wide association studies have identified 57 common variants associated with cardiac structure and function, however, genetic contribution to newer cardiac function measures have not been explored. In addition, few data exist comprehensively characterizing genetic associations (i.e., rare and structural variants) of cardiac structure and function, especially in minorities. Over the past decade, we have investigated the genetic effect on HF and cross-sectional echo measures within the setting of the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium. We now propose to extend our effort to the Trans-Omics for Precision Medicine (TOPMed) Program by combing our rich longitudinal phenotypic data with cutting-edge whole genome sequencing data in seven population-bases cohorts. Our central hypothesis is that specific common, rare and structural genetic variants will be associated with cardiac structure and function, as well as HF; and incorporating genetic predisposition to cardiac structure and function alterations will improve HF risk prediction. In Aim 1, we will characterize genetic architecture of cardiac structure and function and their longitudinal changes, and evaluate their effects on HF. To inform understanding of HF physiology, we will assess the causal effects of proteins and metabolites on echo and HF using Mendelian randomization approaches. In Aim 2, we will construct polygenic risk scores for cardiac structure and function and assess their impact on HF risk prediction. We will apply a new approach for PRS construction, and will use a machine learning algorithms to evaluate its prediction on the risk of HF. With the completion of this project, we aim to generate insights into the biological pathways underlying progressive cardiac dysfunction and HF, and to provide targets for drug development.

心力衰竭（HF）随着年龄的增长而明显增加，并与50%的5年死亡率相关。异常 心脏结构和心脏功能的损害先于HF的发展，并且是HF亚型的基础。 心脏结构和功能是可遗传的-全基因组关联研究已经确定了57种常见的 然而，与心脏结构和功能相关的变异， 尚未探讨措施。此外，很少有数据全面表征遗传 关联（即，罕见和结构变异）的心脏结构和功能，特别是在少数民族。超过 在过去的十年中，我们研究了遗传对HF的影响，并在心脏内进行了横截面回声测量。 基因组流行病学中的心脏和衰老研究（CHARGE）联盟。我们现在 我们建议将我们的努力扩展到Trans-Omics for Precision Medicine（TOPMed）计划， 纵向表型数据和七个人群基础的尖端全基因组测序数据 同伙我们的中心假设是，特定的常见、罕见和结构性遗传变异将与 心脏结构和功能，以及HF;并将遗传易感性纳入心脏结构 和功能改变将改善HF风险预测。在目标1中，我们将描述 心脏结构和功能及其纵向变化，并评估其对HF的影响。通知 了解HF生理学，我们将评估蛋白质和代谢物对回声和HF的因果作用， 使用孟德尔随机化方法。在目标2中，我们将构建心脏结构的多基因风险评分 并评估其对HF风险预测的影响。我们将采用一种新的方法建造生产者责任计划， 并将使用机器学习算法来评估其对HF风险的预测。完成后 这个项目，我们的目标是深入了解进行性心功能不全的生物学途径 和HF，并为药物开发提供靶点。