Abstract MP57: Genetics of Chronic Kidney Disease Stages Across Ancestries: The PAGE Study

Abstract

Background: Chronic kidney disease (CKD) is common, disproportionally burdens ethnic minorities in the US, and is associated with increased cardiovascular mortality. Our prior trans-ethnic genetic research has identified approximately 100 loci for kidney function. We now extend this research to CKD stages in studies of diverse populations. To uncover genetic factors associated CKD stages, we performed genome-wide association studies in diverse populations within the Population Architecture using Genomics and Epidemiology (PAGE) study. Methods: We assembled multi-ethnic data on CKD non-overlapping cases (4,690 mild to moderate CKD, 1,105 advanced CKD [stage 5] including end-stage kidney disease) and non-CKD controls for up to 46,263 PAGE participants (African Americans, Hispanics/Latinos, East Asian, Native Hawaiian and American Indians). We implemented a generalized estimating equation approach for single test genome-wide association analyses using ancestry combined data and adjusting for age, sex, principal components, study and ethnicity. Results: The analyses identified two associated loci at p < 5.3 x 10 -8 , including a novel association with mild to moderate CKD on chromosome 9, which is driven by an intronic variant of TYRP1 (rs186208070, allele frequency 0.01 in our combined sample, 1000 Genomes: 0.02 in AFR, 0.003 AMR, 0.001 EUR, p=4.4 x 10 -8 ). Several genome-wide associated variants at the APOL1 locus were associated with advanced CKD. The most significant finding was for APOL1 G1 rs73885319 (p=1.19 x 10 -9 ). Additional variants with suggestive associations at p<10 -6 for advanced CKD included an intronic low frequency variant in FTO (rs7189997) and a variant nearby IRX3 (rs8050506). Both variants are more common in African ancestry and these loci were previously associated with obesity traits. Conclusions: Our study on the genetics of CKD identified a novel locus for mild to moderate CKD and showed for the first time strong associations of African-ancestry APOL1 variants with advanced CKD across multi-ethnic populations.