Clinical, Genetic, and Proteomic Risk Factors for Pulmonary Hypertension in Heart Failure

心力衰竭肺动脉高压的临床、遗传和蛋白质组学危险因素

• 批准号: 10163899
• 负责人: Evan L Brittain
• 金额: $ 78.78万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-15 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10163899
• 关键词: Address; Affect; African American; American; Automobile Driving; Bioinformatics; Biological; Biometry; Blood Vessels; Clinical; Clinical Practice Guideline; Code; Cohort Studies; Consumption; DNA Repository; Data; Development; Echocardiography; Electronic Health Record; Epidemiology; Event; Financial compensation; Functional disorder; Funding; Genetic; Genetic Risk; Genetic Variation; Genotype; Goals; Gold; Guidelines; Health; Heart failure; Heritability; Incidence; Individual; Inflammatory; Insulin Resistance; Knowledge; Laboratories; Left; Letters; Link; Lung; Measurement; Measures; Medical; Medical Genetics; Metabolic; Molecular; Natural History; Obesity; Outcome; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Plasma; Population; Prospective cohort; Proteins; Proteomics; Pulmonary Hypertension; Pulmonary artery structure; Reporting; Resources; Right Ventricular Dysfunction; Right Ventricular Function; Risk; Risk Factors; Specificity; System; Systolic Pressure; Time; United States Department of Veterans Affairs; Ventricular; Veterans; Woman; base; biobank; cardiometabolism; care seeking; clinical risk; cohort; comorbidity; cost; cost effective; demographics; design; epidemiologic data; genetic association; genome-wide; improved; improved outcome; insight; modifiable risk; mortality; new therapeutic target; precision medicine; preservation; pressure; prevent; programs; protein H(3); protein biomarkers; pulmonary arterial hypertension; racial diversity; trait

PROJECT SUMMARY At least 50% of people with HF develop pulmonary hypertension (HF-PH). The fact that all people with HF have elevated left ventricular filling pressures suggests that there must be additional factors that drive the development of PH. Identifying these factors is important because HF-PH carries a 50% increase in mortality and no treatments exist to improve outcomes or prevent PH development. Epidemiologic data on the risk factors and natural history of HF-PH are lacking. Similarly, the biological mechanisms underlying HF-PH are unknown because no molecular studies have been performed in this population. In addition to establishing incidence rates and clinical risk factors, an important goal of this application is to identify molecular features associated with HF-PH and right ventricular (RV) compensation (i.e. preserved RV function in the setting of PH). We hypothesize that (1) HF-PH incidence rates using echocardiographic data are higher than previously reported rates based on medical codes (2) HF-PH and RV compensation are genetically influenced, and (3) protein biomarkers will be associated with prevalent HF-PH and RV function. These hypotheses are based on our preliminary showing: 1) higher rates of incident HF-PH using echo data than rates based on medical codes alone; 2) association of poor metabolic health with HF-PH and RV dysfunction; 3) high genetic heritability of pulmonary pressure; 4) shared genetic risk between obesity and pulmonary pressure; 5) a genetic association between insulin resistance and PH; and 6) elevation of inflammatory and vascular tone proteins in HF-PH patients. Developing large, prospective cohorts designed to study the natural history of HF-PH would be prohibitively expensive and inefficient. Leveraging electronic health record (EHR)-based cohorts linked to biobanks presents a scientifically valid, cost-effective, and efficient pathway for studying HF-PH epidemiology and pathophysiology. In Aim 1, we will establish HF-PH incidence rates and examine the importance of modifiable risk factors for HF-PH (e.g. obesity, insulin resistance) by extracting echocardiographic PASP values on ~425,000 individuals in the Veterans Affairs and Vanderbilt EHRs (64,000 African Americans and 85,000 women). Approximately 100,000 of these individuals have repeat PASP measurements, and 65,000 have gold standard RHC data. Both cohorts are well phenotyped with detailed data on demographics, comorbidities, medication exposure, laboratory, and clinical events. In Aim 2, we will leverage the VA-funded Million Veterans Program and Vanderbilt's BioVU to analyze genome-wide genotyping data in a total of 25,000 subjects with HF at no cost to this application. In Aim 3, we will perform proteomic profiling (1129 proteins) in discovery (800 subjects) and replication (600 subjects) HF cohorts collected through BioVU. We have combined existing resources with new phenotypic, genotypic, and proteomic data and assembled a team with the specific expertise to execute our aims. If our hypotheses are correct, the results could improve clinical guidelines for HF-PH and identify new therapeutic targets for HF-PH and RV dysfunction.

项目摘要 至少50%的HF患者会发生肺动脉高压（HF-PH）。事实上所有的HF患者 左心室充盈压升高表明，一定有其他因素驱动左心室充盈压升高。 确定这些因素是重要的，因为HF-PH使死亡率增加50 并且不存在改善结果或预防PH发展的治疗。关于风险的流行病学数据 缺乏HF-PH的因素和自然史。同样，HF-PH的生物学机制是 未知，因为尚未在该人群中进行分子研究。除了建立 发病率和临床危险因素，本申请的一个重要目标是鉴定分子特征 与HF-PH和右心室（RV）代偿相关（即， PH）。我们假设（1）使用超声心动图数据的HF-PH发生率高于以前 报告的发生率基于医学代码（2）HF-PH和RV代偿受遗传影响，以及（3） 蛋白质生物标志物将与流行的HF-PH和RV功能相关。这些假设是基于 我们的初步结果显示：1）使用超声数据的HF-PH发生率高于基于医学代码的发生率 2）代谢健康不良与HF-PH和RV功能障碍的相关性; 3）高遗传性 肺压; 4）肥胖和肺压之间共有遗传风险; 5）遗传关联 胰岛素抵抗和PH之间的关系;和6）HF-PH中炎症和血管紧张素蛋白的升高 患者开发旨在研究HF-PH自然史的大型前瞻性队列将是 昂贵得令人望而却步，效率低下。利用基于电子健康记录（EHR）的队列， 生物库为HF-PH流行病学研究提供了一种科学有效、成本效益高且高效的途径 和病理生理学。在目标1中，我们将确定HF-PH的发病率，并检查以下方面的重要性： 通过提取超声心动图PASP，可改变HF-PH的风险因素（例如肥胖、胰岛素抵抗） 退伍军人事务部和范德比尔特EHR中约425，000人的价值观（64，000名非洲裔美国人和 85 000名妇女）。这些人中大约有100，000人重复测量PASP，65，000人重复测量PASP。 拥有黄金标准的RHC数据。两个队列的表型都很好，有详细的人口统计学数据， 合并症、药物暴露、实验室和临床事件。在目标2中，我们将利用VA资助的 百万退伍军人计划和范德比尔特的BioVU分析全基因组基因分型数据，共25000 HF受试者无需为此应用程序支付费用。在目标3中，我们将对1129种蛋白质进行蛋白质组学分析， 通过BioVU收集的发现（800例受试者）和复制（600例受试者）HF队列。我们有 将现有资源与新的表型，基因型和蛋白质组学数据相结合，并组建了一个团队， 执行我们目标的专业知识。如果我们的假设是正确的，结果可以改善临床 HF-PH指南，并确定HF-PH和RV功能障碍的新治疗靶点。