? DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) disproportionately affects African Americans. Two recent discoveries suggest that common, African-specific genetic risk factors are particularly relevant in CKD susceptibility. Variants in the gene encoding apolipoprotein L1 (APOL1) and the presence of a single copy of the sickle cell mutation (sickle cell trait, or SCT) both increase the risk of CKD progression. How these variants confer kidney risk, whether there is gene-gene interplay, and the identity of any causal intermediates is unknown. The proposed studies will use two complementary cohorts of African Americans with CKD, the African American Study of Kidney Disease and Hypertension (AASK) and a subset of BioMe, to investigate these questions. The AASK study is arguably the most comprehensively phenotyped of African Americans with CKD in the world, assessing participants' kidney function every 6 months for up to 12 years (and up to 17 years for end-stage renal disease and death). BioMe is an ongoing, contemporary cohort of patients receiving medical care in New York City, with substantial resources devoted to biospecimen collection and genotyping. The analysis will build upon our prior work in genetic risk factors for CKD by investigating novel variants and their relationship to kidney function decline as well as gene-gene interplay in risk for adverse CKD outcomes. In addition, we will study the relationship of metabolomic patterns - a snapshot of the end-product of cellular processes - with CKD outcomes. This analysis can lead to identification of novel and potentially modifiable risk factors for CKD outcomes. When combined with genomic data, the metabolomic consequences of genetic risk variants such as the APOL1 high-risk genotype or SCT can be studied. In addition, analytic techniques can help distinguish whether metabolomic risk factors cause adverse CKD outcomes or are simply a byproduct of an associated process. Understanding the relationship between genomics, metabolomics, and outcomes will advance knowledge regarding pathogenic pathways and potentially modifiable targets in CKD progression, particularly in African Americans, an ethnic group disproportionately affected with advanced CKD.