TY - JOUR
T1 - Recipient Genotype Is a Predictor of Allograft Cytokine Expression and Outcomes After Pediatric Cardiac Transplantation
AU - Auerbach, Scott R.
AU - Manlhiot, Cedric
AU - Reddy, Sushma
AU - Kinnear, Caroline
AU - Richmond, Marc E.
AU - Gruber, Dorota
AU - McCrindle, Brian W.
AU - Deng, Liyong
AU - Chen, Jonathan M.
AU - Addonizio, Linda J.
AU - Chung, Wendy K.
AU - Mital, Seema
PY - 2009/5/19
Y1 - 2009/5/19
N2 - Objectives: 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)-β, and tumor necrosis factor (TNF)-α 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-β 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.
AB - Objectives: 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)-β, and tumor necrosis factor (TNF)-α 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-β 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.
KW - angiotensin
KW - cardiac transplantation
KW - cytokines
KW - genetics
KW - polymorphism
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U2 - 10.1016/j.jacc.2009.02.027
DO - 10.1016/j.jacc.2009.02.027
M3 - Article
C2 - 19442892
AN - SCOPUS:65549112600
SN - 0735-1097
VL - 53
SP - 1909
EP - 1917
JO - Journal of the American College of Cardiology
JF - Journal of the American College of Cardiology
IS - 20
ER -