Gene expression profiling to study racial differences after heart transplantation
Kiran K. Khush*, Michael X. Pham, Jeffrey J. Teuteberg, Abdallah G. Kfoury, Mario C. Deng, Andrew Kao, Allen S. Anderson, William G. Cotts, Gregory A. Ewald, David A. Baran, David Hiller, James Yee, Hannah A. Valantine
Background The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores. Methods We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race. Results In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels. Conclusions African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups.
Journal of Heart and Lung Transplantation
https://doi.org/10.1016/j.healun.2015.01.987
acute rejection
calcineurin inhibitor
gene expression profile score
10.1016/j.healun.2015.01.987
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Tacrolimus Medicine & Life Sciences
Heart Transplantation Medicine & Life Sciences
Gene Expression Profiling Medicine & Life Sciences
Transcriptome Medicine & Life Sciences
Calcineurin Inhibitors Medicine & Life Sciences
Gene Expression Medicine & Life Sciences
Khush, K. K., Pham, M. X., Teuteberg, J. J., Kfoury, A. G., Deng, M. C., Kao, A., Anderson, A. S., Cotts, W. G., Ewald, G. A., Baran, D. A., Hiller, D., Yee, J., & Valantine, H. A. (2015). Gene expression profiling to study racial differences after heart transplantation. Journal of Heart and Lung Transplantation, 34(7), 970-977. https://doi.org/10.1016/j.healun.2015.01.987
Khush, Kiran K. ; Pham, Michael X. ; Teuteberg, Jeffrey J. ; Kfoury, Abdallah G. ; Deng, Mario C. ; Kao, Andrew ; Anderson, Allen S. ; Cotts, William G. ; Ewald, Gregory A. ; Baran, David A. ; Hiller, David ; Yee, James ; Valantine, Hannah A. / Gene expression profiling to study racial differences after heart transplantation. In: Journal of Heart and Lung Transplantation. 2015 ; Vol. 34, No. 7. pp. 970-977.
@article{256f00da2ef04f228d661ef19ad85008,
title = "Gene expression profiling to study racial differences after heart transplantation",
abstract = "Background The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores. Methods We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race. Results In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels. Conclusions African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups.",
keywords = "acute rejection, calcineurin inhibitor, gene expression profile score, heart transplantation, mortality, race",
author = "Khush, {Kiran K.} and Pham, {Michael X.} and Teuteberg, {Jeffrey J.} and Kfoury, {Abdallah G.} and Deng, {Mario C.} and Andrew Kao and Anderson, {Allen S.} and Cotts, {William G.} and Ewald, {Gregory A.} and Baran, {David A.} and David Hiller and James Yee and Valantine, {Hannah A.}",
note = "Publisher Copyright: {\textcopyright} 2015 International Society for Heart and Lung Transplantation. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.",
doi = "10.1016/j.healun.2015.01.987",
journal = "Journal of Heart and Lung Transplantation",
publisher = "Elsevier USA",
Khush, KK, Pham, MX, Teuteberg, JJ, Kfoury, AG, Deng, MC, Kao, A, Anderson, AS, Cotts, WG, Ewald, GA, Baran, DA, Hiller, D, Yee, J & Valantine, HA 2015, 'Gene expression profiling to study racial differences after heart transplantation', Journal of Heart and Lung Transplantation, vol. 34, no. 7, pp. 970-977. https://doi.org/10.1016/j.healun.2015.01.987
Gene expression profiling to study racial differences after heart transplantation. / Khush, Kiran K.; Pham, Michael X.; Teuteberg, Jeffrey J.; Kfoury, Abdallah G.; Deng, Mario C.; Kao, Andrew; Anderson, Allen S.; Cotts, William G.; Ewald, Gregory A.; Baran, David A.; Hiller, David; Yee, James; Valantine, Hannah A.
In: Journal of Heart and Lung Transplantation, Vol. 34, No. 7, 01.07.2015, p. 970-977.
T1 - Gene expression profiling to study racial differences after heart transplantation
AU - Khush, Kiran K.
AU - Pham, Michael X.
AU - Teuteberg, Jeffrey J.
AU - Kfoury, Abdallah G.
AU - Deng, Mario C.
AU - Kao, Andrew
AU - Anderson, Allen S.
AU - Cotts, William G.
AU - Ewald, Gregory A.
AU - Baran, David A.
AU - Hiller, David
AU - Yee, James
AU - Valantine, Hannah A.
N1 - Publisher Copyright: © 2015 International Society for Heart and Lung Transplantation. Copyright: Copyright 2015 Elsevier B.V., All rights reserved.
N2 - Background The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores. Methods We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race. Results In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels. Conclusions African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups.
AB - Background The basis for increased mortality after heart transplantation in African Americans and other non-Caucasian racial groups is poorly defined. We hypothesized that increased risk of adverse events is driven by biologic factors. To test this hypothesis in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study, we determined whether the event rate of the primary outcome of acute rejection, graft dysfunction, death, or retransplantation varied by race as a function of calcineurin inhibitor (CNI) levels and gene expression profile (GEP) scores. Methods We determined the event rate of the primary outcome, comparing racial groups, stratified by time after transplant. Logistic regression was used to compute the relative risk across racial groups, and linear modeling was used to measure the dependence of CNI levels and GEP score on race. Results In 580 patients monitored for a median of 19 months, the incidence of the primary end point was 18.3% in African Americans, 22.2% in other non-Caucasians, and 8.5% in Caucasians (p < 0.001). There were small but significant correlations of race and tacrolimus trough levels to the GEP score. Tacrolimus levels were similar among the races. Of patients receiving tacrolimus, other non-Caucasians had higher GEP scores than the other racial groups. African American recipients demonstrated a unique decrease in expression of the FLT3 gene in response to higher tacrolimus levels. Conclusions African Americans and other non-Caucasian heart transplant recipients were 2.5-times to 3-times more likely than Caucasians to experience outcome events in the Invasive Monitoring Attenuation through Gene Expression study. The increased risk of adverse outcomes may be partly due to the biology of the alloimmune response, which is less effectively inhibited at similar tacrolimus levels in minority racial groups.
KW - acute rejection
KW - calcineurin inhibitor
KW - gene expression profile score
KW - heart transplantation
KW - mortality
KW - race
U2 - 10.1016/j.healun.2015.01.987
DO - 10.1016/j.healun.2015.01.987
JO - Journal of Heart and Lung Transplantation
JF - Journal of Heart and Lung Transplantation
Khush KK, Pham MX, Teuteberg JJ, Kfoury AG, Deng MC, Kao A et al. Gene expression profiling to study racial differences after heart transplantation. Journal of Heart and Lung Transplantation. 2015 Jul 1;34(7):970-977. https://doi.org/10.1016/j.healun.2015.01.987