Multi-Omics at the Intersections of Environment, Diabetes, and Kidney Disease: A Multi-Omics for Health and Disease Study Site

摘要 终末期肾病(ESKD)是美国人口死亡率的主要贡献者之一。近40% ESKD的发病是由糖尿病引起的，其自然历史包括三个过渡阶段：发展 糖尿病；2.)引发糖尿病肾病(DKD)；以及DKD进展为终末期疾病。 尽管ESKD给公众带来了健康负担，但对慢性肾功能衰竭患者采取干预措施保护肾功能 糖尿病是有限的。黑人和西班牙裔群体面临更高的糖尿病负担和更快的进展 ESKD比白人、非西班牙裔群体更多。健康的社会决定因素(SDOH)和其他环境因素 暴露(例如，金属)是造成这些差异的重要因素。然而，链接的机制 DKD在环境中的暴露尚不清楚。环境数据集成到多组学中的研究 需要一个框架，特别是在黑人和西班牙裔社区，他们患有过度的ESKD和 背负着终生的、不利的环境暴露。我们的目标是建立一个糖尿病和肾脏 疾病研究网站(DSS)由300名不同种族和民族的成年人组成，其中200人 糖尿病(其中一半还患有肾脏疾病)和100名健康对照。我们的DSS将成为 推动应用多组学技术研究健康和疾病的合作倡议 祖先种类繁多的种群。我们将积极与该联盟合作，开展概括性研究。 协议，从参与者招募到综合分析管道，可以共享和 部署在云中。为了成功招募300名研究参与者(目标1)，我们将利用我们已建立的 招聘基础设施，利用创新的遴选战略，将丰富我们的样本，最适合 可能会跨越DKD阶段。30例DKD患者将与UIC肾脏精密中心对口招募 医学项目(KPMP)，支持链接到丰富的KPMP肾脏组织病理学和多组学数据 DKD病例的一个亚样本。我们的样本将反映我们医疗系统的多样性，其中包括一名患者 以非白人为主的人口(约80%)。我们将进一步利用我们广泛的临床研究 收集生物检疫剂并获得有关环境暴露、结果、 和其他协变量，为期三年(目标2)。采集的血液样本将用于进行 所有研究参与者的基因组、表观基因组、转录组、蛋白质组和代谢组谱(目的 3)。利用与财团合作开发的管道和综合分析方案，我们将 确定与环境暴露和肾脏组织病理学有关的分子图谱，并检查它们的 与DKD课程每个阶段的联系(目标4)。我们希望我们的决策支持系统有重要的研究 影响，为综合系统生物学的全面发展贡献了关键信息 DKD的研究方法及新的生物学机制和生物标志物的阐明。

ABSTRACT End stage kidney disease (ESKD) is among the top contributors to mortality in the US population. Nearly 40% of ESKD is caused by diabetes, with a natural history that includes three transitional stages: 1.) Development of diabetes; 2.) Initiation of diabetic kidney disease (DKD); and 3.) Progression of DKD to end-stage disease. Despite the public health burden posed by ESKD, interventions to preserve kidney function in patients with diabetes are limited. Black and Hispanic groups face higher burdens of diabetes and more rapid progression to ESKD than White, non-Hispanic groups. Social determinants of health (SDOH) and other environmental exposures (e.g., metals) are important contributors to these disparities. However, the mechanisms linking environmental exposures to DKD are unclear. Research to integrate environmental data into the multi-omics framework is needed, particularly in Black and Hispanic communities, who suffer from excessive ESKD and are burdened by life-long, adverse environmental exposures. Our goal is to establish a diabetes and kidney disease study site (DSS) comprised of 300 racially and ethnically diverse adults, including 200 with diabetes (half of whom also have kidney disease) and 100 healthy controls. Our DSS will be part of a collaborative initiative to advance the application of multi-omics technologies to study health and disease in ancestrally diverse populations. We will actively engage with this consortium to develop generalizable study protocols, ranging from participant recruitment to integrative analytic pipelines that can be shared and deployed in the cloud. To successfully recruit 300 study participants (Aim 1), we will leverage our established recruitment infrastructure, utilizing an innovative selection strategy that will enrich our sample for those most likely to transition across DKD stages. Thirty DKD cases will be dually recruited with the UIC Kidney Precision Medicine Project (KPMP), enabling linkage to rich KPMP kidney tissue histopathology and multi-omics data in a subsample of DKD cases. Our sample will reflect the diversity of our health system, which includes a patient population that is predominantly non-White (~80%). We will further leverage our extensive clinical research experience to collect biospecimens and obtain detailed information on environmental exposures, outcomes, and other covariables annually for three years (Aim 2). Collected blood specimens will be used to carry-out genomic, epigenomic, transcriptomic, proteomic, and metabolomic profiling among all study participants (Aim 3). Utilizing pipelines and integrative analytic protocols developed in collaboration with the consortium, we will identify molecular profiles linked to environmental exposures and kidney histopathology and examine their associations with each stage of the DKD course (Aim 4). We expect our DSS to have important research impacts, contributing critical information towards the general advancement of integrative systems biology research methods and elucidating novel biological mechanisms and biomarkers for DKD.