title: Recipient genotype is a predictor of allograft cytokine expression and outcomes after pediatric cardiac transplantation.
abstract: OBJECTIVE
  This study sought to investigate the influence of recipient renin-angiotensin-aldosterone system (RAAS) genotype on cardiac function, rejection, and outcomes after heart transplantation.
  
  
  BACKGROUND
  The RAAS influences cardiac function and up-regulates inflammatory/immune pathways. Little is known about the effect of recipient RAAS polymorphisms in pediatric cardiac transplantation.
  
  
  METHODS
  Patients <25 years of age, after cardiac transplantation, were enrolled (2003 to 2008) and genotyped for polymorphisms in genes associated with RAAS upregulation: AGT-G, ACE-D, AGTR1-C, CYP11B2-G, and CMA-A. Presence of at least 1 high-risk allele was defined as a high-risk genotype. Univariable and multivariable associations between genotypes and outcomes were assessed in time-dependent models using survival, logistic, or linear regression models. Biopsy samples were immunostained for interleukin (IL)-6, transforming growth factor (TGF)-beta, and tumor necrosis factor (TNF)-alpha during rejection and quiescence.
  
  
  RESULTS
  A total of 145 patients were studied, 103 primary cohort and 42 replication cohort; 81% had rejection, 51% had graft dysfunction, and 13% had vasculopathy, 7% died and 8% underwent re-transplantation. A higher number of homozygous high-risk RAAS genotypes was associated with a higher risk of graft dysfunction (hazard ratio [HR]: 1.5, p = 0.02) and a higher probability of death (HR: 2.5, p = 0.04). The number of heterozygous high-risk RAAS genotypes was associated with frequency of rejection (+0.096 events/year, p < 0.001) and rejection-associated graft dysfunction (+0.37 events/year, p = 0.002). IL-6 and TGF-beta were markedly upregulated during rejection in patients with >/=2 high-risk RAAS genotypes.
  
  
  CONCLUSIONS
  Recipient RAAS polymorphisms are associated with a higher risk of rejection, graft cytokine expression, graft dysfunction, and a higher mortality after cardiac transplantation. This may have implications for use of RAAS inhibitors in high-risk patients after transplantation.
authors.affiliation: Department of Pediatric Cardiology, Columbia University, Morgan Stanley Children's Hospital of New York-Presbyterian, New York, New York, USA.
authors.forename: Scott R
authors.initials: SR
authors.lastname: Auerbach
authors.forename: Cedric
authors.initials: C
authors.lastname: Manlhiot
authors.forename: Sushma
authors.initials: S
authors.lastname: Reddy
authors.forename: Caroline
authors.initials: C
authors.lastname: Kinnear
authors.forename: Marc E
authors.initials: ME
authors.lastname: Richmond
authors.forename: Dorota
authors.initials: D
authors.lastname: Gruber
authors.forename: Brian W
authors.initials: BW
authors.lastname: McCrindle
authors.forename: Liyong
authors.initials: L
authors.lastname: Deng
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Chen
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Addonizio
authors.forename: Wendy K
authors.initials: WK
authors.lastname: Chung
authors.forename: Seema
authors.initials: S
authors.lastname: Mital
mesh_terms: D001706:Biopsy; D009202:Cardiomyopathies / Q000601:surgery; D002648:Child; D004247:DNA / Q000235:genetics*; D004452:Echocardiography; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D005838:Genotype; D006084:Graft Rejection / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D006330:Heart Defects, Congenital / Q000601:surgery; D016027:Heart Transplantation; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics*; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D016133:Polymerase Chain Reaction; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis / Q000235:genetics*; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics*; D014184:Transplantation, Homologous
chemical_list: D015850:Interleukin-6; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D004247:DNA