Recipient Genotype Is a Predictor of Allograft Cytokine Expression and Outcomes After Pediatric Cardiac Transplantation

Scott R. Auerbach, Cedric Manlhiot, Sushma Reddy, Caroline Kinnear, Marc E. Richmond, Dorota Gruber, Brian W. McCrindle, Liyong Deng, Jonathan M. Chen, Linda J. Addonizio, Wendy K. Chung, Seema Mital

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1909-1917
Number of pages9
JournalJournal of the American College of Cardiology
Volume53
Issue number20
DOIs
StatePublished - May 19 2009
Externally publishedYes

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Heart Transplantation
Renin-Angiotensin System
Allografts
Genotype
Pediatrics
Cytokines
Graft Rejection
Transforming Growth Factors
Transplants
Linear Models
Interleukin-6
Up-Regulation
Transplantation
Cytochrome P-450 CYP11B2
Dilatation and Curettage
Tumor Necrosis Factor-alpha
Logistic Models
Alleles
Biopsy
Survival

Keywords

  • angiotensin
  • cardiac transplantation
  • cytokines
  • genetics
  • polymorphism

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

Cite this

Recipient Genotype Is a Predictor of Allograft Cytokine Expression and Outcomes After Pediatric Cardiac Transplantation. / Auerbach, Scott R.; Manlhiot, Cedric; Reddy, Sushma; Kinnear, Caroline; Richmond, Marc E.; Gruber, Dorota; McCrindle, Brian W.; Deng, Liyong; Chen, Jonathan M.; Addonizio, Linda J.; Chung, Wendy K.; Mital, Seema.

In: Journal of the American College of Cardiology, Vol. 53, No. 20, 19.05.2009, p. 1909-1917.

Research output: Contribution to journalArticle

Auerbach, SR, Manlhiot, C, Reddy, S, Kinnear, C, Richmond, ME, Gruber, D, McCrindle, BW, Deng, L, Chen, JM, Addonizio, LJ, Chung, WK & Mital, S 2009, 'Recipient Genotype Is a Predictor of Allograft Cytokine Expression and Outcomes After Pediatric Cardiac Transplantation', Journal of the American College of Cardiology, vol. 53, no. 20, pp. 1909-1917. https://doi.org/10.1016/j.jacc.2009.02.027
Auerbach, Scott R. ; Manlhiot, Cedric ; Reddy, Sushma ; Kinnear, Caroline ; Richmond, Marc E. ; Gruber, Dorota ; McCrindle, Brian W. ; Deng, Liyong ; Chen, Jonathan M. ; Addonizio, Linda J. ; Chung, Wendy K. ; Mital, Seema. / Recipient Genotype Is a Predictor of Allograft Cytokine Expression and Outcomes After Pediatric Cardiac Transplantation. In: Journal of the American College of Cardiology. 2009 ; Vol. 53, No. 20. pp. 1909-1917.
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abstract = "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.",
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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

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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.

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