MicroRNAs as Biomarkers of Heart Transplant Rejection
MicroRNAs as Biomarkers of Heart Transplant Rejection
Aim Rejection is one of the major causes of late cardiac allograft failure and at present can only be diagnosed by invasive endomyocardial biopsies. We sought to determine whether microRNA profiling could serve as a non-invasive biomarker of cardiac allograft rejection.
Methods We included 113 heart transplant recipients from four referral French institutions (test cohort, n = 60, validation cohort, n = 53). In the test cohort, we compared patients with acute biopsy-proven allograft rejection (n = 30) to matched control patients without rejection (n = 30), by assessing microRNAs expression in the heart allograft tissue and patients concomitant serum using RNA extraction and qPCR analysis. Fourteen miRNAs were selected on the basis of their implication in allograft rejection, endothelial activation, and inflammation and tissue specificity.
Results We identified seven miRNAs that were differentially expressed between normal and rejecting heart allografts: miR-10a, miR-21, miR-31, miR-92a, miR-142-3p miR-155, and miR-451 (P < 0.0001 for all comparisons). Four out of seven miRNAs also showed differential serological expression (miR-10a, miR-31, miR-92a, and miR-155) with strong correlation with their tissular expression. The receiver-operating characteristic analysis showed that these four circulating miRNAs strongly discriminated patients with allograft rejection from patients without rejection: miR-10a (AUC = 0.975), miR-31 (AUC = 0.932), miR-92a (AUC = 0.989), and miR-155 (AUC = 0.998, P < 0.0001 for all comparisons). We confirmed in the external validation set that these four miRNAs highly discriminated patients with rejection from those without. The discrimination capability of the four miRNAs remained significant when stratified by rejection diagnosis (T-cell-mediated rejection or antibody-mediated rejection) and time post-transplant.
Conclusion This study demonstrates that a differential expression of miRNA occurs in rejecting allograft patients, not only at the tissue level but also in the serum, suggesting their potential relevance as non-invasive biomarkers in heart transplant rejection.
Heart transplantation is a life-saving treatment for patients with end-stage heart failure, which represents a severe burden worldwide. Despite considerable advances in transplantation, allograft rejection remains a major issue leading to allograft loss and mortality.
Currently, the gold standard for diagnosing and monitoring acute heart rejection relies on multiple and repeated endomyocardial biopsies (EMB) performed for acute clinical indications (heart failure, decrease in left ventricular function) or carried out on a regular basis in patients in a steady state in order to screen for subclinical rejection. Despite their usefulness, EMB remains an invasive procedure associated with rare but potentially serious complications, discomfort for the patients and increased cost for the community.
Identifying non-invasive and reliable biomarkers for screening heart transplant rejection is one of the major challenges of solid organ transplantation. While attempts have been made to isolate such biomarkers using peripheral blood gene expression in low-risk heart transplant recipients, this question is still unanswered.
A recent breakthrough has occurred with the discovery of small and non-coding RNAs called microRNAs that regulate gene expression. Though miRNAs are known to be involved in many biological processes such as development, cell proliferation, differentiation, apoptosis, and oncogenesis; emerging data suggest that they may play a critical role in the regulation of immune cell development and in the modulation of innate and adaptive immune responses. Consequently, miRNAs have become a potential interest in the field of organ transplant rejection.
In the present study, we hypothesized that specific miRNAs could be used as relevant biomarkers for heart transplant rejection. We sought to identify a miRNA signature in rejecting heart allografts and to determine whether assessment of miRNAs post-transplant could serve as non-invasive biomarkers of heart transplant rejection. Such information could have a major impact on the clinical management of heart transplant recipients.
Abstract and Introduction
Abstract
Aim Rejection is one of the major causes of late cardiac allograft failure and at present can only be diagnosed by invasive endomyocardial biopsies. We sought to determine whether microRNA profiling could serve as a non-invasive biomarker of cardiac allograft rejection.
Methods We included 113 heart transplant recipients from four referral French institutions (test cohort, n = 60, validation cohort, n = 53). In the test cohort, we compared patients with acute biopsy-proven allograft rejection (n = 30) to matched control patients without rejection (n = 30), by assessing microRNAs expression in the heart allograft tissue and patients concomitant serum using RNA extraction and qPCR analysis. Fourteen miRNAs were selected on the basis of their implication in allograft rejection, endothelial activation, and inflammation and tissue specificity.
Results We identified seven miRNAs that were differentially expressed between normal and rejecting heart allografts: miR-10a, miR-21, miR-31, miR-92a, miR-142-3p miR-155, and miR-451 (P < 0.0001 for all comparisons). Four out of seven miRNAs also showed differential serological expression (miR-10a, miR-31, miR-92a, and miR-155) with strong correlation with their tissular expression. The receiver-operating characteristic analysis showed that these four circulating miRNAs strongly discriminated patients with allograft rejection from patients without rejection: miR-10a (AUC = 0.975), miR-31 (AUC = 0.932), miR-92a (AUC = 0.989), and miR-155 (AUC = 0.998, P < 0.0001 for all comparisons). We confirmed in the external validation set that these four miRNAs highly discriminated patients with rejection from those without. The discrimination capability of the four miRNAs remained significant when stratified by rejection diagnosis (T-cell-mediated rejection or antibody-mediated rejection) and time post-transplant.
Conclusion This study demonstrates that a differential expression of miRNA occurs in rejecting allograft patients, not only at the tissue level but also in the serum, suggesting their potential relevance as non-invasive biomarkers in heart transplant rejection.
Introduction
Heart transplantation is a life-saving treatment for patients with end-stage heart failure, which represents a severe burden worldwide. Despite considerable advances in transplantation, allograft rejection remains a major issue leading to allograft loss and mortality.
Currently, the gold standard for diagnosing and monitoring acute heart rejection relies on multiple and repeated endomyocardial biopsies (EMB) performed for acute clinical indications (heart failure, decrease in left ventricular function) or carried out on a regular basis in patients in a steady state in order to screen for subclinical rejection. Despite their usefulness, EMB remains an invasive procedure associated with rare but potentially serious complications, discomfort for the patients and increased cost for the community.
Identifying non-invasive and reliable biomarkers for screening heart transplant rejection is one of the major challenges of solid organ transplantation. While attempts have been made to isolate such biomarkers using peripheral blood gene expression in low-risk heart transplant recipients, this question is still unanswered.
A recent breakthrough has occurred with the discovery of small and non-coding RNAs called microRNAs that regulate gene expression. Though miRNAs are known to be involved in many biological processes such as development, cell proliferation, differentiation, apoptosis, and oncogenesis; emerging data suggest that they may play a critical role in the regulation of immune cell development and in the modulation of innate and adaptive immune responses. Consequently, miRNAs have become a potential interest in the field of organ transplant rejection.
In the present study, we hypothesized that specific miRNAs could be used as relevant biomarkers for heart transplant rejection. We sought to identify a miRNA signature in rejecting heart allografts and to determine whether assessment of miRNAs post-transplant could serve as non-invasive biomarkers of heart transplant rejection. Such information could have a major impact on the clinical management of heart transplant recipients.
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