Gene expression profiling and racial disparities in outcomes after heart transplantation

Yasbanoo Moayedi, Chun Po S. Fan, Robert J.H. Miller, Maxime Tremblay-Gravel, Juan G.Duero Posada, Cedric Manlhiot, D. Hiller, J. Yee, Robert Woodward, Jennifer A. McCaughan, Michael A. Shullo, Shelley A. Hall, Sean Pinney, Kiran K. Khush, Heather J. Ross, Jeffrey J. Teuteberg

Research output: Contribution to journalArticle

Abstract

BACKGROUND: African Americans (AAs) have lower survival rates after heart transplantation (HTx) than Caucasians. The aim of this analysis was to evaluate racial differences in gene expression and their associations with survival and the composite outcome of death, retransplant, rejection with hemodynamic compromise, and graft dysfunction in the Outcomes AlloMap Registry. METHODS: Registry participants included low-risk Caucasian and AA heart transplant recipients with a baseline and at least 1 follow-up gene expression test (AlloMap(C)) within the first year after HTx. The Kaplan-Meier method with delayed entry was used to describe differences in outcomes. Multivariable Cox hazard regression was used to evaluate the associations of overall gene expression profiling score, MARCH8 and FLT3 expression, and tacrolimus levels with each outcome, and stratified Cox models were developed to quantify race-specific associations. RESULTS: Among 933 eligible recipients, 737 (79%) were Caucasian and 196 (21%) were AA. Compared with Caucasians, AAs were significantly younger (55 vs 59 years, p < 0.001), with higher rates of non-ischemic cardiomyopathy (68% vs 50%, p < 0.001), sensitization (>10% panel reactive antibody, 16% vs 9.1%, p = 0.009), and human leukocyte antigen mismatches (7 vs 7, p = 0.01), but less frequent primary cytomegalovirus serostatus mismatch (14.31% vs 27.3%, p < 0.001). Overall, AAs had an increased adjusted mortality risk (hazard ratio [HR] 4.13, p = 0.007). Higher tacrolimus levels were associated with decreased mortality in AAs (HR 0.62, p = 0.009). Overall gene expression profiling score was associated with increased mortality among Caucasians (HR 1.21, p = 0.048). In Caucasians, but not AAs, overexpression of MARCH8 was associated with increased mortality (HR 2.90, p = 0.001). FLT3 upregulation was associated with increased mortality (HR 2.42, p = 0.033) in AAs. There was an inverse relationship between FLT3 expression and tacrolimus levels (-0.029 and -0.176, respectively) in Caucasians and AAs. CONCLUSIONS: AAs have a significantly higher mortality risk after HTx than Caucasians, even in the low-risk Outcomes AlloMap Registry population. AAs and Caucasians had differential outcomes based upon the varying expression of MARCH8 and FLT3 genes following HTx.

Original languageEnglish (US)
Pages (from-to)820-829
Number of pages10
JournalJournal of Heart and Lung Transplantation
Volume38
Issue number8
DOIs
StatePublished - Aug 1 2019
Externally publishedYes

Fingerprint

Gene Expression Profiling
Heart Transplantation
African Americans
Mortality
Tacrolimus
Registries
Gene Expression
HLA Antigens
Cytomegalovirus
Proportional Hazards Models
Up-Regulation
Survival Rate
Hemodynamics
Odds Ratio
Transplants

Keywords

  • gene expression profiling
  • graft failure
  • heart transplantation
  • race/ethnicity
  • survival

ASJC Scopus subject areas

  • Surgery
  • Pulmonary and Respiratory Medicine
  • Cardiology and Cardiovascular Medicine
  • Transplantation

Cite this

Moayedi, Y., Fan, C. P. S., Miller, R. J. H., Tremblay-Gravel, M., Posada, J. G. D., Manlhiot, C., ... Teuteberg, J. J. (2019). Gene expression profiling and racial disparities in outcomes after heart transplantation. Journal of Heart and Lung Transplantation, 38(8), 820-829. https://doi.org/10.1016/j.healun.2019.05.008

Gene expression profiling and racial disparities in outcomes after heart transplantation. / Moayedi, Yasbanoo; Fan, Chun Po S.; Miller, Robert J.H.; Tremblay-Gravel, Maxime; Posada, Juan G.Duero; Manlhiot, Cedric; Hiller, D.; Yee, J.; Woodward, Robert; McCaughan, Jennifer A.; Shullo, Michael A.; Hall, Shelley A.; Pinney, Sean; Khush, Kiran K.; Ross, Heather J.; Teuteberg, Jeffrey J.

In: Journal of Heart and Lung Transplantation, Vol. 38, No. 8, 01.08.2019, p. 820-829.

Research output: Contribution to journalArticle

Moayedi, Y, Fan, CPS, Miller, RJH, Tremblay-Gravel, M, Posada, JGD, Manlhiot, C, Hiller, D, Yee, J, Woodward, R, McCaughan, JA, Shullo, MA, Hall, SA, Pinney, S, Khush, KK, Ross, HJ & Teuteberg, JJ 2019, 'Gene expression profiling and racial disparities in outcomes after heart transplantation', Journal of Heart and Lung Transplantation, vol. 38, no. 8, pp. 820-829. https://doi.org/10.1016/j.healun.2019.05.008
Moayedi, Yasbanoo ; Fan, Chun Po S. ; Miller, Robert J.H. ; Tremblay-Gravel, Maxime ; Posada, Juan G.Duero ; Manlhiot, Cedric ; Hiller, D. ; Yee, J. ; Woodward, Robert ; McCaughan, Jennifer A. ; Shullo, Michael A. ; Hall, Shelley A. ; Pinney, Sean ; Khush, Kiran K. ; Ross, Heather J. ; Teuteberg, Jeffrey J. / Gene expression profiling and racial disparities in outcomes after heart transplantation. In: Journal of Heart and Lung Transplantation. 2019 ; Vol. 38, No. 8. pp. 820-829.
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abstract = "BACKGROUND: African Americans (AAs) have lower survival rates after heart transplantation (HTx) than Caucasians. The aim of this analysis was to evaluate racial differences in gene expression and their associations with survival and the composite outcome of death, retransplant, rejection with hemodynamic compromise, and graft dysfunction in the Outcomes AlloMap Registry. METHODS: Registry participants included low-risk Caucasian and AA heart transplant recipients with a baseline and at least 1 follow-up gene expression test (AlloMap(C)) within the first year after HTx. The Kaplan-Meier method with delayed entry was used to describe differences in outcomes. Multivariable Cox hazard regression was used to evaluate the associations of overall gene expression profiling score, MARCH8 and FLT3 expression, and tacrolimus levels with each outcome, and stratified Cox models were developed to quantify race-specific associations. RESULTS: Among 933 eligible recipients, 737 (79{\%}) were Caucasian and 196 (21{\%}) were AA. Compared with Caucasians, AAs were significantly younger (55 vs 59 years, p < 0.001), with higher rates of non-ischemic cardiomyopathy (68{\%} vs 50{\%}, p < 0.001), sensitization (>10{\%} panel reactive antibody, 16{\%} vs 9.1{\%}, p = 0.009), and human leukocyte antigen mismatches (7 vs 7, p = 0.01), but less frequent primary cytomegalovirus serostatus mismatch (14.31{\%} vs 27.3{\%}, p < 0.001). Overall, AAs had an increased adjusted mortality risk (hazard ratio [HR] 4.13, p = 0.007). Higher tacrolimus levels were associated with decreased mortality in AAs (HR 0.62, p = 0.009). Overall gene expression profiling score was associated with increased mortality among Caucasians (HR 1.21, p = 0.048). In Caucasians, but not AAs, overexpression of MARCH8 was associated with increased mortality (HR 2.90, p = 0.001). FLT3 upregulation was associated with increased mortality (HR 2.42, p = 0.033) in AAs. There was an inverse relationship between FLT3 expression and tacrolimus levels (-0.029 and -0.176, respectively) in Caucasians and AAs. CONCLUSIONS: AAs have a significantly higher mortality risk after HTx than Caucasians, even in the low-risk Outcomes AlloMap Registry population. AAs and Caucasians had differential outcomes based upon the varying expression of MARCH8 and FLT3 genes following HTx.",
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T1 - Gene expression profiling and racial disparities in outcomes after heart transplantation

AU - Moayedi, Yasbanoo

AU - Fan, Chun Po S.

AU - Miller, Robert J.H.

AU - Tremblay-Gravel, Maxime

AU - Posada, Juan G.Duero

AU - Manlhiot, Cedric

AU - Hiller, D.

AU - Yee, J.

AU - Woodward, Robert

AU - McCaughan, Jennifer A.

AU - Shullo, Michael A.

AU - Hall, Shelley A.

AU - Pinney, Sean

AU - Khush, Kiran K.

AU - Ross, Heather J.

AU - Teuteberg, Jeffrey J.

PY - 2019/8/1

Y1 - 2019/8/1

N2 - BACKGROUND: African Americans (AAs) have lower survival rates after heart transplantation (HTx) than Caucasians. The aim of this analysis was to evaluate racial differences in gene expression and their associations with survival and the composite outcome of death, retransplant, rejection with hemodynamic compromise, and graft dysfunction in the Outcomes AlloMap Registry. METHODS: Registry participants included low-risk Caucasian and AA heart transplant recipients with a baseline and at least 1 follow-up gene expression test (AlloMap(C)) within the first year after HTx. The Kaplan-Meier method with delayed entry was used to describe differences in outcomes. Multivariable Cox hazard regression was used to evaluate the associations of overall gene expression profiling score, MARCH8 and FLT3 expression, and tacrolimus levels with each outcome, and stratified Cox models were developed to quantify race-specific associations. RESULTS: Among 933 eligible recipients, 737 (79%) were Caucasian and 196 (21%) were AA. Compared with Caucasians, AAs were significantly younger (55 vs 59 years, p < 0.001), with higher rates of non-ischemic cardiomyopathy (68% vs 50%, p < 0.001), sensitization (>10% panel reactive antibody, 16% vs 9.1%, p = 0.009), and human leukocyte antigen mismatches (7 vs 7, p = 0.01), but less frequent primary cytomegalovirus serostatus mismatch (14.31% vs 27.3%, p < 0.001). Overall, AAs had an increased adjusted mortality risk (hazard ratio [HR] 4.13, p = 0.007). Higher tacrolimus levels were associated with decreased mortality in AAs (HR 0.62, p = 0.009). Overall gene expression profiling score was associated with increased mortality among Caucasians (HR 1.21, p = 0.048). In Caucasians, but not AAs, overexpression of MARCH8 was associated with increased mortality (HR 2.90, p = 0.001). FLT3 upregulation was associated with increased mortality (HR 2.42, p = 0.033) in AAs. There was an inverse relationship between FLT3 expression and tacrolimus levels (-0.029 and -0.176, respectively) in Caucasians and AAs. CONCLUSIONS: AAs have a significantly higher mortality risk after HTx than Caucasians, even in the low-risk Outcomes AlloMap Registry population. AAs and Caucasians had differential outcomes based upon the varying expression of MARCH8 and FLT3 genes following HTx.

AB - BACKGROUND: African Americans (AAs) have lower survival rates after heart transplantation (HTx) than Caucasians. The aim of this analysis was to evaluate racial differences in gene expression and their associations with survival and the composite outcome of death, retransplant, rejection with hemodynamic compromise, and graft dysfunction in the Outcomes AlloMap Registry. METHODS: Registry participants included low-risk Caucasian and AA heart transplant recipients with a baseline and at least 1 follow-up gene expression test (AlloMap(C)) within the first year after HTx. The Kaplan-Meier method with delayed entry was used to describe differences in outcomes. Multivariable Cox hazard regression was used to evaluate the associations of overall gene expression profiling score, MARCH8 and FLT3 expression, and tacrolimus levels with each outcome, and stratified Cox models were developed to quantify race-specific associations. RESULTS: Among 933 eligible recipients, 737 (79%) were Caucasian and 196 (21%) were AA. Compared with Caucasians, AAs were significantly younger (55 vs 59 years, p < 0.001), with higher rates of non-ischemic cardiomyopathy (68% vs 50%, p < 0.001), sensitization (>10% panel reactive antibody, 16% vs 9.1%, p = 0.009), and human leukocyte antigen mismatches (7 vs 7, p = 0.01), but less frequent primary cytomegalovirus serostatus mismatch (14.31% vs 27.3%, p < 0.001). Overall, AAs had an increased adjusted mortality risk (hazard ratio [HR] 4.13, p = 0.007). Higher tacrolimus levels were associated with decreased mortality in AAs (HR 0.62, p = 0.009). Overall gene expression profiling score was associated with increased mortality among Caucasians (HR 1.21, p = 0.048). In Caucasians, but not AAs, overexpression of MARCH8 was associated with increased mortality (HR 2.90, p = 0.001). FLT3 upregulation was associated with increased mortality (HR 2.42, p = 0.033) in AAs. There was an inverse relationship between FLT3 expression and tacrolimus levels (-0.029 and -0.176, respectively) in Caucasians and AAs. CONCLUSIONS: AAs have a significantly higher mortality risk after HTx than Caucasians, even in the low-risk Outcomes AlloMap Registry population. AAs and Caucasians had differential outcomes based upon the varying expression of MARCH8 and FLT3 genes following HTx.

KW - gene expression profiling

KW - graft failure

KW - heart transplantation

KW - race/ethnicity

KW - survival

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