The role of renin-angiotensin-aldosterone system genes in the progression of chronic kidney disease: findings from the Chronic Renal Insufficiency Cohort (CRIC) study

• Published in: Nephrology, dialysis, transplantation Vol. 30; no. 10; pp. 1711 - 1718
• Main Authors: Kelly, Tanika N, Raj, Dominic, Rahman, Mahboob, Kretzler, Matthias, Kallem, Radhakrishna R, Ricardo, Ana C, Rosas, Sylvia E, Tao, Kaixiang, Xie, Dawei, Hamm, Lotuce Lee, He, Jiang
• Format: Journal Article
• Language: English
• Published: England 01.10.2015
• Subjects: Adult; Aged; Biomarkers - analysis; Cohort Studies; Disease Progression; Female; Genotype; Glomerular Filtration Rate; Humans; Kidney Failure, Chronic - diagnosis; Kidney Failure, Chronic - genetics; Male; Middle Aged; Polymorphism, Single Nucleotide - genetics; Proportional Hazards Models; Renin-Angiotensin System - genetics; Young Adult; chronic kidney disease; genetics; renin–angiotensin–aldosterone system
• ISSN: 0931-0509; 1460-2385
• DOI: 10.1093/ndt/gfv125

We conducted single-marker, gene- 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 study participants. A total of 1523 white and 1490 black subjects were genotyped for 490 single nucleotide polymorphisms (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. Among white and black participants, eGFR declined an average of 1.2 and 2.3 mL/min/1.73 m(2)/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 (both P < 1.00 × 10(-6)). Driven by the significant gene-based findings, the entire RAAS pathway was also associated with renal events in both groups (both P < 1.00 × 10(-6)). No single-marker associations with CKD progression were observed. The current study provides strong evidence for a role of the RAAS in CKD progression.