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

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.