Proteomic discovery in an inception cohort of acute myocardial infarction survivors

摘要 虽然人们对冠心病(CHD)的病因从基因和基因方面都有很多了解 实验研究，对冠心病复发的原因和新的治疗策略知之甚少 二级预防出现得很慢。高通量基于亲和力的蛋白质组学现在允许 对大种群中数百种甚至数千种蛋白质的评估，最近的研究表明 这种方法可以导致发现与各种心血管疾病相关的新蛋白质。 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 提高对冠心病复发病因的认识，找出新的致病因素 为冠心病二级预防提供潜在的治疗靶点。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 1575名急性心肌梗死(AMI)幸存者的初始队列中的血浆蛋白，验证 在长达16年的随访中复发的CHD事件，并评估纵向蛋白与 复发的冠心病风险。HVH研究拥有Gwas数据和丰富的心血管危险因素信息， 来自电子数据库和医疗记录的合并症、急性心肌梗死后干预和用药情况。 使用适当的研究将最大限度地减少疾病复发研究中的潜在偏差来源 设计和统计方法。来自人类免疫缺陷病毒研究和更大外部人群的基因组数据 将被用于为孟德尔随机化实验选择强大的遗传决定因素，这将 评估蛋白质与冠心病复发风险之间的关系是否可能是因果关系。对于最高优先级 从发现分析中出现的蛋白质，我们将使用廉价的靶向免疫分析来验证 在基于人群的队列和最近急性白血病患者的研究中，对蛋白质和复制关联进行研究 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 在发生急性心肌梗死的幸存者中复制偶然蛋白与复发冠心病的关联。目标2是使用 这种方法可以确定新的蛋白质与二次结局(心力衰竭、心房颤动、 和死亡率)。由于在跟踪过程中事件数量众多，我们具有出色的识别能力 主要目标(HR 1.19)和次要目标(HR 1.16-1.29)的蛋白质关联。这样的效率 方法可以加速发现冠心病二级预防的新治疗靶点，这 是目前所缺乏的。

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.