Aptamer Proteomics of Cardiometabolic and Renal Traits in African Americans

心脏代谢性疾病和慢性肾脏疾病(CKD)的负担在 非裔美国人(AA)，但负责任的环境和/或遗传机制还不完全 已定义。对选定的血浆蛋白进行定量是有临床价值的，这里提出了新的发现。 强有力的是，扩大分析的蛋白质阵列可以提供对发病机制的新见解，并提供 疾病风险和事件的新标记。为了解决重要的知识差距，我们建议分析一个 杰克逊心脏研究(JHS)和南方大学的AA患者血浆样本中前所未有的一系列蛋白质 社区队列研究(SCCS)。我们将测试蛋白质组学的总体假设-- 表型队列将确定在再生障碍性贫血中特别重要的新的致病途径。 在具体目标1中，我们建议进行横断面研究，以确定心脏代谢的新的蛋白质组生物标志物。 和肾脏特征。在特定目标2中，我们将评估基线血浆蛋白浓度是否可以预测 发生冠心病(CHD)和慢性肾脏病。对于具体目标1和2，JHS将是发现 队列；横断面和纵向研究结果将在SCCS中得到临床验证。在具体目标3中，我们 将使用GWAS、外显子组序列和全基因组序列来探索 与心脏代谢性疾病和慢性肾脏病相关的蛋白质，并将测试是否存在 在大型荟萃分析中，与蛋白质水平相关的因素可预测冠心病和慢性肾脏病的发病情况。 我们将利用一个强大的新分析平台，在这个平台中，单链DNA分子称为适配子 已被修改为对1,310个靶向血浆蛋白阵列具有高亲和力和特异性。这个 适配子与每种蛋白质的浓度成比例地结合，并通过荧光释放和定量， 使用微阵列。我们提出了这些分析的广泛的实验验证，包括正交法 用液相色谱-质谱法进行验证。我们在JHS，BIDMC，BROAD的多学科团队 范德比尔特大学带来了蛋白质组学、生物标记物、遗传和种群方面的专业知识 流行病学、生物信息学和健康差距。所有数据都将向公众开放，提供 为科学界提供独特而宝贵的资源。

There is a disproportionate burden of cardiometabolic disease and chronic kidney disease (CKD) among African Americans (AA), but the responsible environmental and/or genetic mechanisms are incompletely defined. Quantitation of selected plasma proteins is clinically valuable, and new findings presented here argue strongly that broadening the array of proteins analyzed can provide new insight into pathogenesis and offer novel markers of disease risk and events. To address important knowledge gaps, we propose to analyze an unprecedented array of proteins in plasma samples of AA in the Jackson Heart Study (JHS) and the Southern Community Cohort Study (SCCS). We will test the overall hypothesis that proteomic profiling in well- phenotyped cohorts will identify new pathogenic pathways of particular importance in AA. In Specific Aim 1, we propose cross-sectional studies to identify novel proteomic biomarkers of cardiometabolic and renal traits. In Specific Aim 2, we will assess whether baseline plasma protein concentrations predict incident coronary heart disease (CHD) and CKD. For Specific Aims 1 and 2 the JHS will be the discovery cohort; cross-sectional and longitudinal findings will be clinically validated in the SCCS. In Specific Aim 3, we will use GWAS, exome sequence, and whole genome sequence to explore the genetic determinants of proteins that are associated with cardiometabolic disease and CKD, and will test whether variants that are associated with protein levels predict incident CHD and CKD in large meta-analyses. We will leverage a powerful new analytic platform in which single-stranded DNA molecules called aptamers have been modified to have high avidity and specificity for an array of 1,310 targeted plasma proteins. The aptamers bind in proportion to each protein's concentration, and are released and quantified by fluorescence, using microarrays. We present extensive experimental validation of these analyses including orthogonal validation by liquid chromatography-mass spectrometry. Our multi-disciplinary team at the JHS, BIDMC, Broad Institute, and Vanderbilt University brings expertise in proteomics, biomarkers, genetic and population epidemiology, bioinformatics, and health disparities. All data will be made publically available, providing a unique and valuable resource to the scientific community.