title: 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- 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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  The current study provides strong evidence for a role of the RAAS in CKD progression.
authors.affiliation: School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA.
authors.forename: Tanika N
authors.initials: TN
authors.lastname: Kelly
authors.affiliation: Medical Faculty Associates, George Washington University, Washington, DC 20037, USA.
authors.forename: Dominic
authors.initials: D
authors.lastname: Raj
authors.affiliation: University Hospitals Case Medical Center, Case Western Reserve University, Louis Stokes Cleveland VA Medical Center, Cleveland, OH 44106, USA.
authors.forename: Mahboob
authors.initials: M
authors.lastname: Rahman
authors.affiliation: University of Michigan, Ann Arbor, MI 48109, USA.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kretzler
authors.affiliation: University of Pennsylvania, Translational Research Center, Philadelphia, PA 19104, USA.
authors.forename: Radhakrishna R
authors.initials: RR
authors.lastname: Kallem
authors.affiliation: University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Ricardo
authors.affiliation: Joslin Diabetes Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sylvia E
authors.initials: SE
authors.lastname: Rosas
authors.affiliation: The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Kaixiang
authors.initials: K
authors.lastname: Tao
authors.affiliation: The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Dawei
authors.initials: D
authors.lastname: Xie
authors.affiliation: Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Lotuce Lee
authors.initials: LL
authors.lastname: Hamm
authors.affiliation: School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA 70112, USA Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors.forename: Jiang
authors.initials: J
authors.lastname: He
mesh_terms: D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000032:analysis*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D005838:Genotype; D005919:Glomerular Filtration Rate; D006801:Humans; D007676:Kidney Failure, Chronic / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D016016:Proportional Hazards Models; D012084:Renin-Angiotensin System / Q000235:genetics*; D055815:Young Adult
chemical_list: D015415:Biomarkers
keywords: chronic kidney disease; genetics; renin–angiotensin–aldosterone system