Multi-Omics for Chronic Kidney Disease

PROJECT SUMMARY Chronic kidney disease (CKD) is a common complex condition associated with high morbidity and mortality, with a prevalence estimated at 13% in the U.S. that continues to increase annually. The etiology of CKD is complex, with both genetic – including monogenetic and polygenic – and environmental contributions playing major roles. African American and Hispanic communities in the U.S. are disproportionally affected by CKD; environmental, socioeconomic, and inherited factors, such as APOL1 risk genotypes, are likely contributing to these disparities. Multi-omic approaches including genetics, epigenetics, transcriptomics, proteomics, and metabolomics are high- throughput technologies being leveraged for precision medicine that hold great potential to improve diagnosis and clinical care for complex diseases such as CKD. As part of the Multi-omics Health and Disease Consortium, this proposal will establish a Disease Study Site (DSS) focused on CKD. Our rationale for selecting CKD is three- fold: 1) CKD has high cost and public health impact in the U.S. and disproportionally affects minority populations underrepresented in genomic research; 2) CKD represents an important modifier of multi-omic profiles in other common conditions; and 3) there is an urgent, unmet need to provide molecular disease subclassification in CKD – and in particular non-diabetic CKD – as the current diagnosis relies solely on functional rather than molecular criteria. Our hypothesis is that longitudinal blood and urine multi-omics can provide non-invasive means to better subclassify non-diabetic CKD, and thus provide a new precision medicine-based approach for this condition. In alignment with the mission of the consortium, our DSS also aims to address current disparities in kidney disease and genomics, considering that individuals of non-European ancestry are overwhelming under-represented in human genetic and multi-omic studies of kidney disease. To this end, we propose a prospective study of 200 CKD patients and 100 non-CKD controls of diverse ancestral backgrounds, with at least 75% of participants from groups underrepresented in research. We will address the following questions: What are the molecular correlates of longitudinal decline in renal function in ancestrally diverse patients? Are there specific molecular subtypes of non-diabetic CKD identifiable by longitudinal multi-omics? What are the roles of environmental exposures, social and economic stressors, and genetics in determining molecular CKD subtypes? Our team involves national leaders in Precision Medicine and has a track record of successful execution of genetic, epidemiologic, and interventional studies involving diverse underrepresented populations. We will coordinate efficient local recruitment of our prospective cohort using innovative outreach methods that address barriers to recruiting under-represented groups. Our long-term goal is to promote health equity and challenge the existing clinical paradigms in CKD and multi-omics more broadly to advance precision medicine.