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

项目总结 慢性肾脏病(CKD)影响着全球5亿人，老年人的负担最重 成年人。慢性肾脏病患者不仅罹患终末期肾病的风险增加，而且患心血管疾病的风险也增加。 疾病、心力衰竭和死亡。现有的慢性肾脏病的治疗方法是不够的，而且有大量的、糟糕的治疗方法。 了解疾病进展中的异质性。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，以及分子 已识别的变异体如何调控疾病的基础仍未解释。 我们的主要假设是，一种结合遗传学、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。疾病的可变性 可能部分是由于DNA甲基化的可变性，它会随着年龄和代谢环境的变化而变化， 修改基因表达。高通量技术的进步彻底改变了网络的广度和 代谢组学和蛋白质组学分析的精确度，使人们能够前所未有地打开了解基因组网络的窗口。 这项研究的目的是使用系统生物学的方法将遗传序列变异与 DNA甲基化模式、蛋白质组学和代谢组学，以促进我们对DNA甲基化模式的理解和 慢性肾脏病风险的治疗。 拟议的拨款将用于研究影响持续动脉粥样硬化中慢性肾脏病风险的生物途径。 风险社区(ARIC)研究，这是一项以社区为基础的当代白人和黑人成年人队列研究 70岁以上，计划在两个CKD队列中复制，并进一步扩展到肾脏组织。这个 丰富的表型、全面的判定结果和遗传、表观基因组学的组合(由 这笔赠款)、蛋白质组和代谢组数据提供了一个独特的机会来深入了解 CKD的分子基础，改进CKD的风险预测，并确定一系列候选途径和基因 其产品可能成为药物开发的靶点。 我们的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 肾功能和代谢物、蛋白质及相关途径(目标1)，确定特定途径 洞察CKD相关结局，包括CKD进展、心力衰竭、心血管疾病 疾病和死亡率(目标2)，并阐明这些候选者背后的遗传和表观遗传变异 路径(目标3)。这项研究将使用创新方法和组学数据相结合的方法来确定路径 和遗传变异是临床相关的，因此对风险预测和潜在的 慢性肾脏病患者的治疗。

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.