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）随着年龄的增长而增加，与50％的5年死亡率有关。异常 心脏结构和心脏功能的损害先于HF和HF亚型的发展。 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个常见 然而，与心脏结构和功能相关的变体，对新的心脏功能的遗传贡献 尚未探索措施。此外，很少有数据全面表征遗传 心脏结构和功能的关联（即稀有和结构变体），尤其是在少数群体中。超过 在过去的十年中，我们研究了对HF和横截面回声措施的遗传作用 为基因组流行病学（电荷）联盟中心脏和衰老研究的同类群体设置。我们现在 建议通过梳理我们的富人来将我们的努力扩展到精密医学（TopMed）计划的跨词 纵向表型数据，具有七个种群基因组的尖端整个基因组测序数据 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 具有心脏结构和功能以及HF；并融入心脏结构的遗传易感性 功能改变将改善HF风险预测。在AIM 1中，我们将表征 心脏结构和功能及其纵向变化，并评估其对HF的影响。告知 了解HF生理学，我们将评估蛋白质和代谢物对回声和HF的因果关系 使用孟德尔随机方法。在AIM 2中，我们将为心脏结构构建多基因风险评分 功能并评估其对HF风险预测的影响。我们将采用一种新方法来进行PRS构造， 并将使用机器学习算法评估其对HF风险的预测。完成 这个项目，我们旨在产生对进步性心脏功能障碍潜在的生物学途径的见解 和HF，并为药物开发提供目标。