PROJECT SUMMARY This is an application by an early stage investigator who has the long-term objective of studying determinants of racial and ethnic disparities in kidney disease. Risk variants in the Apolipoprotein L1 (APOL1) gene on chromosome 22 are common in persons of African ancestry (African Americans and Afro-Caribbean Hispanic Americans) and are one of the most powerful disease variants identified to date in terms of frequency and effect size. This is an important discovery for kidney disease and has furthered our understanding of racial/ethnic disparities in kidney disease. There are efforts underway to incorporate APOL1 genetic testing in clinical settings including in pre-transplant evaluation and targeted therapies are on the horizon. However, the presence of two risk variants (i.e. the APOL1 high-risk genotypes, seen in up to 14% of African Americans and 4% of Afro-Caribbean Hispanic Americans) does not lead to overt kidney disease in all individuals. This incomplete penetrance indicates a major role of either genetic or environmental modifiers i.e. ‘second hits’. Although some genetic modifiers have been discovered, previous studies have been hampered by lack of sample sizes due to underrepresentation of minorities. There are also strong associations between air pollution, adverse neighborhood environment (including walkability and poverty) and podocyte toxic heavy metals (Arsenic, Cadmium and Mercury) with kidney disease and racial/ethnic minorities are disproportionately exposed to these environmental risk factors. We propose a robust research strategy leveraging several large datasets/cohorts to comprehensively investigate the genetic and environmental ‘second-hits’ for the APOL1- kidney disease association through the following Specific Aims: : To identify and replicate SNPs that modify the association of the APOL1 high-risk genotypes with kidney disease (Aim 1). Using genetic and clinical data on ~70,000 minority individuals (~5,400 with APOL1 high-risk genotypes), we will investigate SNPs modifying the association between APOL1 high-risk genotype and kidney disease. We will then perform replication of the top performing hits in ~25,000 independent individuals (~5,000 with APOL1 high-risk genotypes). We will then assess the interaction of air pollution (particulate matter<2.5 µg or PM2.5) and adverse measures of neighborhood walkability/poverty with APOL1 high-risk for kidney disease (Aim 2) using geographically diverse studies: BioMe Biobank; Jackson Heart Study and REasons for Geographic and Racial Differences in Stroke (REGARDS) in ~40,000 individuals (~3,600 with APOL1 high-risk genotypes). Finally, we will explore the interaction between urine levels of Arsenic, Cadmium and Mercury with APOL1 high-risk genotypes for kidney disease in a case-control study from REGARDS (n=2,332) and in exploratory analyses assess whether soluble urokinase-type plasminogen activator receptor (suPAR) levels-an inflammatory APOL1 modifier-affects this interaction (Aim 3). This proposal will lead to critical insights on genetic and environmental ‘second hits’ for APOL1 and improved understanding of racial/ethnic disparities in kidney disease.

PROJECT NARRATIVE. Mutations in a specific gene (Apolipoprotein L1 or APOL1) seen only in people of African ancestry (African Americans or Hispanic Americans) is linked to high rates of kidney disease, with only some of the individuals with these mutations developing kidney disease, indicating that other genetic or environmental factors are involved. We will explore these factors including other genes and common environmental exposures like air pollution/neighborhood environment, and heavy metal exposure. We will understand what additional risk factors contribute to kidney disease in individuals with this mutation, which will lead to preventative efforts to address the persistent racial and ethnic disparities in kidney disease.