Identifying 4 Novel lncRNAs as Potential Biomarkers for Acute Rejection and Graft Loss of Renal Allograft

Abstract

Acute rejection (AR) after kidney transplant is one of the major obstacles to obtain ideal graft survival. Reliable molecular biomarkers for AR and renal allograft loss are lacking. This study was performed to identify novel long noncoding RNAs (lncRNAs) for diagnosing AR and predicting the risk of graft loss. The several microarray datasets with AR and nonrejection specimens of renal allograft downloaded from Gene Expression Omnibus database were analyzed to screen differentially expressed lncRNAs (DElncRNAs) and mRNAs (DEmRNAs). Univariate and multivariate Cox regression analyses were used to identify optimal prognosis-related DElncRNAs for constructing a risk score model. 39 common DElncRNAs and 185 common DEmRNAs were identified to construct a lncRNA-mRNA regulatory relationship network. DElncRNAs were revealed to regulate immune cell activation and proliferation. Then, 4 optimal DElncRNAs, ATP1A1-AS1, CTD-3080P12.3, EMX2OS, and LINC00645, were selected from 17 prognostic DElncRNAs to establish the 4-lncRNA risk score model. In the training set, the high-risk patients were more inclined to graft loss than the low-risk patients. Time-dependent receiver operating characteristics analysis revealed the model had good sensitivity and specificity in prediction of 1-, 2-, and 3-year graft survival after biopsy ( $\text{AUC}=0.891,0.836,\text{and}0.733$ , respectively). The internal testing set verified the result well. Gene set enrichment analysis which expounded NOD-like receptor, the Toll-like receptor signaling pathways, and other else playing important role in immune response was enriched by the 4 lncRNAs. Allograft-infiltrating immune cells analysis elucidated the expression of 4 lncRNAs correlated with gamma delta T cells and eosinophils, etc. Our study identified 4 novel lncRNAs as potential biomarkers for AR of renal allograft and constructed a lncRNA-based model for predicting the risk of graft loss, which would provide new insights into mechanisms of AR.