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: 10676123
• 负责人: James S Floyd
• 金额: $ 69.33万
• 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/10676123
• 关键词: Acceleration; Acute myocardial infarction; Affinity; African American; Aspirin; Atrial Fibrillation; Biological Assay; Biological Markers; Biological Process; Blood Platelets; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Chronic Disease; Coronary heart disease; Data; Databases; Disease; Effectiveness; Electronics; Etiology; Evaluation; Event; Genetic Determinism; Genetic study; Genomics; Goals; Health; Healthcare Systems; Heart; Heart failure; Immunoassay; Incidence; Intervention; Jackson Heart Study; LDL Cholesterol Lipoproteins; Measures; Medical Records; Mendelian randomization; Methods; Monoclonal Antibodies; Participant; Patients; Pharmaceutical Preparations; Plasma; Plasma Proteins; Population; Population Study; Primary Prevention; Prospective, cohort study; Proteins; Proteomics; Recurrence; Recurrent disease; Research Design; Risk; Risk Reduction; Sampling; Secondary Prevention; Source; Specificity; Statistical Methods; Survivors; Therapeutic; Validation; Variant; acute coronary syndrome; 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; novel therapeutic intervention; population based; primary outcome; protein biomarkers; secondary outcome; study population; therapeutic target

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 虽然对遗传和遗传和 实验研究，对CHD复发的原因和新的治疗策略的了解少得多 次要预防的出现缓慢。基于高通量亲和力的蛋白质组学现在允许 评估大量人群中数百甚至数千种蛋白质，最近的研究表明这一点 方法可能导致发现与各种心血管疾病相关的新型蛋白质。 此外，基因组数据的整合和使用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因子因素之间。该项目的目标是使用蛋白质组学 提高我们对复发性冠心病病因的理解，并确定是新因果因素的蛋白质 和潜在预防冠心病的潜在治疗靶标。心脏和血管健康（HVH） 研究，我们建议使用基于接近性扩展测定法的蛋白质组学平台来测量1,160 急性心肌梗死（AMI）的1,575个幸存者的血浆蛋白质蛋白质的血浆蛋白 在最多16年的随访期间，经常性的冠心病事件，并评估与纵向蛋白的关联 经常性冠心病风险。 HVH研究具有GWAS数据和有关心血管危险因素的丰富信息， 电子数据库和病历中的合并症以及AMI后干预和药物使用。 使用适当的研究将最小化疾病复发研究中的偏见来源 设计和统计方法。来自HVH研究和较大外部人群的基因组数据 将用于选择孟德尔随机实验的强遗传决定因素，这将 评估与复发性冠心病风险的蛋白质关联是否可能是因果关系。最高优先级 从发现分析中出现的蛋白质，我们将使用廉价的目标免疫测定来验证 蛋白质并复制基于人群的队列和最近急性患者的研究 冠状动脉综合征。该项目的目标1是使用蛋白质组学和基因组数据来识别，验证和 在事件AMI的幸存者中，复制随意蛋白质的蛋白质关联。目标2是使用 这种方法是鉴定与继发结果的新型蛋白质相关的方法（心力衰竭，房颤， 和死亡率）。由于随访期间发生了大量事件，我们具有出色的能力来识别 主要目的（HR 1.19）和次级目的（HR 1.16-1.29）的蛋白质关联。这个高效 方法可以加速发现新的治疗靶标，以预防冠心病，这 目前缺乏。

项目成果

Association Between Diabetes Severity and Risks of COVID-19 Infection and Outcomes.

• DOI: 10.1007/s11606-023-08076-9
• 发表时间: 2023-05
• 期刊: JOURNAL OF GENERAL INTERNAL MEDICINE
• 影响因子: 5.7
• 作者: Floyd, James S.;Walker, Rod L.;Kuntz, Jennifer L.;Shortreed, Susan M.;Fortmann, Stephen P.;Bayliss, Elizabeth A.;Harrington, Laura B.;Fuller, Sharon;Albertson-Junkans, Ladia H.;Powers, John D.;Lee, Mi H.;Temposky, Lisa A.;Dublin, Sascha
• 通讯作者: Dublin, Sascha