Abstract 01: The Role of Renin-Angiotensin-Aldosterone System Genes in the Progression of Chronic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study

Abstract

Background: We conducted single-marker, gene-based and pathway-based analyses to examine the association between renin-angiotensin-aldosterone system (RAAS) variants and chronic kidney disease (CKD) progression among Chronic Renal Insufficiency Cohort (CRIC) study participants. Methods: A total of 1,523 white and 1,490 black subjects were genotyped for 490 SNPs in 12 RAAS genes as part of the ITMAT-Broad-CARe array. CKD progression phenotypes included decline in estimated glomerular filtration rate (eGFR) over time and the occurrence of a renal disease event, defined as incident end stage renal disease or halving of eGFR from baseline. Mixed-effects models were used to examine SNP associations with eGFR decline, while Cox proportional hazards models tested SNP associations with renal events. Gene and pathway-based analyses were conducted using the truncated product method. All analyses were stratified by race, and a Bonferroni correction was applied to adjust for multiple testing. Results: Among white and black participants, eGFR declined an average of 1.2 and 2.3 ml/min/1.73m 2 per year, respectively, while renal events occurred in a respective 11.5% and 24.9% of participants. We identified strong gene and pathway-based associations with CKD progression. The AGT and RENBP genes were consistently associated with risk of renal events in separate analyses of white and black participants (all P <1.00х10 -6 ). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P <1.00х10 -6 ). No single-marker associations with CKD progression were observed. Conclusions: The current study provides strong evidence for a role of the RAAS in CKD progression.