Proteomic discovery in an inception cohort of acute myocardial infarction survivors

摘要 虽然从遗传学和免疫学角度对冠心病的病因学了解很多， 实验研究，对冠心病复发的原因知之甚少，新的治疗策略 二级预防出现缓慢。高通量的基于亲和性的蛋白质组学现在允许 在大群体中评估数百甚至数千种蛋白质，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 蛋白质生物标志物和致病因素之间的联系。该项目的目标是利用蛋白质组学， 提高我们对复发性CHD病因学的理解，并确定新的致病因素蛋白质 是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个 血浆蛋白在1,575例急性心肌梗死（AMI）幸存者的初始队列中，验证 在长达16年的随访期间，观察CHD事件的复发，并评估与 CHD复发风险HVH研究拥有GWAS数据和丰富的心血管危险因素信息， 合并症、AMI后干预和药物使用。 通过使用适当的研究，将疾病复发研究中的潜在偏倚源降至最低 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化实验的强遗传决定因素，这将 评估蛋白质与冠心病复发风险的关联是否可能是因果关系。用于最高优先级 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 在基于人群的队列和近期急性脑梗死患者的研究中， 冠状动脉综合征该项目的目标1是利用蛋白质组学和基因组学数据来识别，验证， 在急性心肌梗死幸存者中复制偶发蛋白与冠心病复发的相关性。目标2：使用 该方法用于鉴定与次要结果（心力衰竭，心房纤颤， 死亡率）。由于随访期间的事件数量众多，我们有很好的识别能力 主要目的（HR 1.19）和次要目的（HR 1.16 - 1.29）的蛋白质关联。这种高效 这种方法可以加速发现冠心病二级预防的新治疗靶点， 目前缺乏。

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.