Proteomic discovery in an inception cohort of acute myocardial infarction survivors

急性心肌梗死幸存者初始队列中的蛋白质组学发现

• 批准号: 10057101
• 负责人: James S Floyd
• 金额: $ 81.15万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-15 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057101
• 关键词: Acute myocardial infarction; Affinity; African American; Aftercare; Aspirin; Atrial Fibrillation; Biological Assay; Biological Markers; Biological Process; Cardiovascular Diseases; Cardiovascular system; Chronic Disease; Coronary heart disease; Data; Databases; Disease; Effectiveness; Etiology; Evaluation; Event; Genetic Determinism; Genetic study; Genomics; Goals; Health; Healthcare Systems; Heart failure; Immunoassay; Incidence; Intervention; Jackson Heart Study; LDL Cholesterol Lipoproteins; Lead; Measures; Medical Records; Methods; Monoclonal Antibodies; Participant; Patients; Pharmaceutical Preparations; Plasma; Plasma Proteins; Population; Population Study; Primary Prevention; Prospective cohort study; Proteins; Proteomics; Randomized; Recurrence; Recurrent disease; Research Design; Risk; Sampling; Secondary Prevention; Source; Specificity; Statistical Methods; Survivors; Therapeutic; Validation; Variant; acute coronary syndrome; base; candidate validation; cardiovascular health; cardiovascular risk factor; cohort; comorbidity; design; disorder risk; experimental study; follow-up; genome wide association study; genomic data; heart disease risk; improved; mortality; new therapeutic target; novel; population based; primary outcome; protein biomarkers; secondary outcome; study population; therapeutic target; treatment strategy

ABSTRACT While much is known about the etiology of incident coronary heart disease (CHD) from genetic and experimental studies, far less is known about the causes of CHD recurrence, and new treatment strategies for secondary prevention have been slow to emerge. High-throughput affinity-based proteomics now allows for an evaluation of hundreds or even thousands of proteins in large populations, and recent studies suggest that this approach can lead to the discovery of novel proteins associated with various cardiovascular diseases. Moreover, the integration of genomic data and use of Mendelian randomization methods can help distinguish between protein biomarkers and causal factors for disease. The goals of this project are to use proteomics to improve our understanding of the etiology of recurrent CHD, and to identify proteins that are new causal factors and potential therapeutic targets for the secondary prevention of CHD. In the Heart and Vascular Health (HVH) Study, we propose to use a proteomics platform based on the proximity extension assay to measure 1,160 plasma proteins in an inception cohort of 1,575 survivors of an acute myocardial infarction (AMI), validate recurrent CHD events during up to 16 years of follow up, and evaluate longitudinal protein associations with recurrent CHD risk. The HVH Study has GWAS data and rich information on cardiovascular risk factors, comorbidities, and post-AMI interventions and medication use from electronic databases and medical records. Potential sources of bias in studies of disease recurrence will be minimized with the use of appropriate study designs and statistical approaches. Genomic data from the HVH Study and from larger external populations will be used to select strong genetic determinants for Mendelian randomization experiments, which will evaluate whether protein associations with recurrent CHD risk are likely to be causal. For the highest priority proteins that emerge from the discovery analyses, we will use inexpensive targeted immunoassays to validate proteins and to replicate associations in population-based cohorts and in studies of patients with recent acute coronary syndrome. Aim 1 of this project is to use proteomic and genomic data to identify, validate, and replicate casual protein associations with recurrent CHD among survivors of an incident AMI. Aim 2 is to use this approach to identify novel protein associations with secondary outcomes (heart failure, atrial fibrillation, and mortality). Because of the large number of events during follow up, we have excellent power to identify protein associations for both the primary aim (HR 1.19) and secondary aims (HR 1.16-1.29). This efficient approach can accelerate the discovery of new therapeutic targets for the secondary prevention of CHD, which are currently lacking.

抽象的 尽管人们对冠心病 (CHD) 的病因学有很多了解，但从遗传和 实验研究表明，对于冠心病复发的原因以及新的治疗策略知之甚少。 二级预防的出现进展缓慢。基于高通量亲和力的蛋白质组学现在允许 对大量人群中数百甚至数千种蛋白质进行评估，最近的研究表明，这 该方法可以导致与各种心血管疾病相关的新型蛋白质的发现。 此外，基因组数据的整合和孟德尔随机化方法的使用可以帮助区分 蛋白质生物标志物与疾病致病因素之间的关系。该项目的目标是利用蛋白质组学 提高我们对复发性冠心病病因的理解，并识别新的致病因素蛋白质 以及冠心病二级预防的潜在治疗靶点。心脏和血管健康 (HVH) 研究中，我们建议使用基于邻近延伸分析的蛋白质组学平台来测量 1,160 在 1,575 名急性心肌梗塞 (AMI) 幸存者的初始队列中检测血浆蛋白，验证 在长达 16 年的随访期间反复发生 CHD 事件，并评估纵向蛋白质关联 复发性冠心病风险。 HVH 研究拥有 GWAS 数据和有关心血管危险因素的丰富信息， 通过电子数据库和医疗记录了解合并症、AMI 后干预措施和药物使用情况。 通过使用适当的研究，可以最大限度地减少疾病复发研究中潜在的偏倚来源 设计和统计方法。来自 HVH 研究和更大的外部人群的基因组数据 将用于为孟德尔随机化实验选择强遗传决定因素，这将 评估蛋白质与复发性冠心病风险是否可能存在因果关系。对于最高优先级 对于发现分析中出现的蛋白质，我们将使用廉价的靶向免疫测定来验证 蛋白质并在基于人群的队列和近期急性发作患者的研究中复制关联 冠状动脉综合征。该项目的目标 1 是使用蛋白质组和基因组数据来识别、验证和 在 AMI 幸存者中复制偶然蛋白质与复发性 CHD 的关联。目标 2 是使用 这种方法可以识别与次要结果（心力衰竭、心房颤动、 和死亡率）。由于随访期间发生的事件数量众多，我们有极强的能力来识别 主要目标（HR 1.19）和次要目标（HR 1.16-1.29）的蛋白质关联。这种高效 该方法可以加速发现冠心病二级预防的新治疗靶点， 目前还缺乏。