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）是美国人群死亡率的主要原因之一。近四成 ESKD是由糖尿病引起的，其自然史包括三个过渡阶段：1.发展 糖尿病; 2.）糖尿病肾病（DKD）的开始;和3.）DKD进展为终末期疾病。 尽管ESKD造成了公共卫生负担，但在ESKD患者中保护肾功能的干预措施仍然存在。 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， ESKD高于白色、非西班牙裔组。健康的社会决定因素和其他环境因素 暴露（例如，金属）是造成这些差异的重要因素。然而，联系机制 DKD的环境暴露尚不清楚。研究将环境数据纳入多组学 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， 承受着终生的不良环境暴露的负担。我们的目标是建立一个糖尿病和肾脏 疾病研究中心（DSS）由300名不同种族和民族的成年人组成，包括200名 糖尿病患者（其中一半患有肾脏疾病）和100名健康对照者。我们的DSS将是一个 合作倡议，以促进多组学技术的应用，以研究健康和疾病， 祖先不同的人群。我们将积极与该联盟合作，开展可推广的研究 协议，从参与者招募到可以共享的综合分析管道， 部署在云中。为了成功招募300名研究参与者（目标1），我们将利用我们现有的 招聘基础设施，利用创新的选择策略，将丰富我们的样本，为那些最 可能会在DKD阶段之间过渡。将通过UIC Kidney Precision招募30例DKD病例 医学项目（KPMP），能够链接到丰富的KPMP肾组织组织病理学和多组学数据， DKD病例的子样本。我们的样本将反映我们卫生系统的多样性，其中包括一名病人， 主要是非白人（约80%）。我们将进一步利用我们广泛的临床研究 收集生物样本和获得环境暴露、结果 和其他协变量每年三年（目标2）。采集的血液标本将用于 所有研究参与者的基因组、表观基因组、转录组、蛋白质组和代谢组分析（Aim 3）。利用与该联盟合作开发的管道和综合分析协议，我们将 确定与环境暴露和肾脏组织病理学相关的分子谱，并检查其 与DKD课程每个阶段的关联（目标4）。我们希望我们的DSS有重要的研究 影响，为综合系统生物学的全面发展提供关键信息 研究方法和阐明DKD的新生物学机制和生物标志物。

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.