Identification of Candidate Biomarkers for Transplant Rejection from Transcriptome Data: A Systematic Review

Background: Traditional methods for rejection control in transplanted patients are considered invasive, risky, and prone to sampling errors. Using molecular biomarkers as an alternative protocol to biopsies, for monitoring rejection may help to mitigate some of these problems, increasing the survival rates and well-being of patients. Recent advances in omics technologies provide an opportunity for screening new molecular biomarkers to identify those with clinical utility.

Objective: This systematic literature review (SLR) aimed to summarize existing evidence derived from large-scale expression profiling regarding differentially expressed mRNA and miRNA in graft rejection, highlighting potential molecular biomarkers in transplantation.

Methods: The study was conducted following PRISMA methodology and the BiSLR guide for performing SLR in bioinformatics. PubMed, ScienceDirect, and EMBASE were searched for publications from January 2001 to January 2018, and studies (i) aiming at the identification of transplant rejection biomarkers, (ii) including human subjects, and (iii) applying methodologies for differential expression analysis from large-scale expression profiling were considered eligible. Differential expression patterns reported for genes and miRNAs in rejection were summarized from both cross-organ and organ-specific perspectives, and pathways enrichment analysis was performed for candidate biomarkers to interrogate their functional role in transplant rejection.

Results: A total of 821 references were collected, resulting in 604 studies after removal of duplicates. After application of inclusion and exclusion criteria, 33 studies were included in our analysis. Among the 1517 genes and 174 miRNAs identifed, CXCL9, CXCL10, STAT1, hsa-miR-142-3p, and hsa-miR-155 appeared to be particularly promising as biomarkers in transplantation, with an increased expression associated with transplant rejection in multiple organs. In addition, hsa-miR-28-5p was consistently decreased in samples taken from rejected organs.

Conclusion: Despite the need for further research to fill existing knowledge gaps, transcriptomic technologies have a relevant role in the discovery of accurate biomarkers for transplant rejection diagnostics. Studies have reported consistent evidence of differential expression associated with transplant rejection, although issues such as experimental heterogeneity hinder a more systematic characterization of observed molecular changes. Special attention has been giving to large-scale mRNA expression profiling in rejection, whereas there is still room for improvements in the characterization of miRnome in this condition.

Prospero Registration Number: CRD42018083321.