Integrative Omics, Chronic Kidney Disease, and Adverse Outcomes in Older Adults

项目摘要 慢性肾脏疾病（CKD）影响着全球5亿人，其中老年人的负担最大 成年人了CKD患者不仅患终末期肾病的风险增加，而且心血管疾病的风险也增加。 疾病心力衰竭和死亡目前对CKD的治疗是不够的，而且有大量的， 了解疾病进展的异质性。虽然全基因组关联研究已经确定 调节CKD相关风险的遗传变异，CKD的大部分遗传性，以及 然而，对于已确定的变异如何调节疾病的基础，仍然无法解释。 我们的总体假设是，一个综合的方法结合遗传学，表观遗传学，蛋白质组学， 代谢组学可以为CKD的发病机制和预后提供新的见解。疾病变异性 可能部分是由于DNA甲基化的变异性，它随着年龄和代谢环境的变化而变化， 修饰基因表达。高通量技术的进步已经彻底改变了 代谢组学和蛋白质组学分析的精确性，使前所未有的窗口进入transomic网络。 本研究的目的是使用系统生物学方法整合基因序列变异与 DNA甲基化模式，蛋白质组学和代谢组学，以促进我们的理解， 治疗CKD风险。 拟议的拨款将在正在进行的动脉粥样硬化研究中研究影响CKD风险的生物学途径。 风险社区（ARIC）研究，一个当代的，以社区为基础的队列的白色和黑人成年人现在年龄 70岁及以上，计划在两个CKD队列中进行复制，并进一步扩展至肾组织。的 结合丰富的表型，全面的裁定结果，和遗传，表观基因组（由 这项拨款），蛋白质组学和代谢组学数据提供了一个独特的机会，以产生洞察力， CKD的分子基础，改善CKD风险预测，并确定一系列候选途径和基因 其产品可以作为药物开发的目标。 长期目标是改善慢性肾脏病患者的护理，我们的目标是发现慢性肾脏病患者与慢性肾脏病患者之间的关系。 肾功能和代谢物，蛋白质和相关途径（目标1），确定特定的途径， 深入了解CKD相关结局，包括CKD进展、心力衰竭、心血管 疾病和死亡率（目标2），并阐明这些候选人的遗传和表观遗传变异 路径（目标3）。该研究将使用创新方法和组学数据相结合的方法来确定途径 和遗传变异是临床相关的，因此在告知风险预测和潜在的 治疗CKD患者。

PROJECT SUMMARY Chronic kidney disease (CKD) affects 500 million people worldwide, with the greatest burden among older adults. People with CKD are at elevated risk for not only end-stage kidney disease, but also cardiovascular disease, heart failure, and death. Existing treatment for CKD is inadequate, and there is vast, poorly understood heterogeneity in disease progression. While genome-wide association studies have identified genetic variants that modulate CKD-associated risk, much of the hereditability of CKD, as well as the molecular basis for how identified variants regulate disease, remains unexplained. Our overarching hypothesis is that an integrated approach combining genetics, epigenetics, proteomics, and metabolomics can yield novel insights into the pathogenesis and prognosis of CKD. Variability in disease may be due in part to variability in DNA methylation, which changes with age and the metabolic milieu and can modify gene expression. Advances in high-throughput technology have revolutionized the breadth and precision of metabolomic and proteomic profiling, enabling unprecedented windows into trans-omic networks. The objective of this study is to use a systems biology approach to integrate genetic sequence variation with DNA methylation patterns, proteomics, and metabolomics in order to advance our understanding and treatment of CKD risk. The proposed grant will pursue biological pathways that affect CKD risk in the ongoing Atherosclerosis Risk Communities (ARIC) study, a contemporary, community-based cohort of white and black adults now aged 70 years and older, with plan for replication in two CKD cohorts and further extension to kidney tissue. The combination of rich phenotyping, comprehensive adjudicated outcomes, and genetic, epigenomic (funded by this grant), proteomic, and metabolomic data provides a unique opportunity to generate insights into the molecular basis of CKD, improve CKD risk prediction, and identify a series of candidate pathways and genes whose products may serve as targets for drug development. With the long-term goal of improving care in patients with CKD, we aim to discover associations between kidney function and metabolites, proteins, and related pathways (Aim 1), identifying specific pathways that provide insight into CKD-associated outcomes, including CKD progression, heart failure, cardiovascular disease, and mortality (Aim 2), and elucidate genetic and epigenetic variation underlying these candidate pathways (Aim 3). The study will use a combination of innovative methods and omics data to identify pathways and genetic variation that are clinical relevant and thus useful in informing the risk prediction and potentially treatment of patients with CKD.