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. 2017 Dec 1;7(1):16751.
doi: 10.1038/s41598-017-17146-y.

Screening and identification of lncRNAs as potential biomarkers for pulmonary tuberculosis

Zhong-Liang Chen  1 , Li-Liang Wei  2 , Li-Ying Shi  3 , Meng Li  3 , Ting-Ting Jiang  4 , Jing Chen  1 , Chang-Ming Liu  1 , Su Yang  1 , Hui-Hui Tu  1 , Yu-Ting Hu  4 , Lin Gan  4 , Lian-Gen Mao  1 , Chong Wang  1 , Ji-Cheng Li  5   6
Affiliations

Screening and identification of lncRNAs as potential biomarkers for pulmonary tuberculosis

Zhong-Liang Chen et al. Sci Rep. .

Abstract

Pulmonary tuberculosis (TB) is among the diseases with the highest morbidity and mortality worldwide. Effective diagnostic methods for TB are lacking. In this study, we investigated long non-coding RNAs (lncRNAs) in plasma using microarray and the potential diagnostic value of lncRNAs for TB. We found a total of 163 up-regulated lncRNAs and 348 down-regulated lncRNAs. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) and coding-noncoding co-expression (CNC) analyses showed that functions of differentially expressed lncRNAs were mainly enriched in the regulation of alpha-beta T cell activation and the T cell receptor signalling pathway. Four differentially expressed lncRNAs, NR_038221 (fold change = 3.79, P < 0.01), NR_003142 (fold change = 1.69, P < 0.05), ENST00000570366 (fold change = 3.04, P < 0.05), and ENST00000422183 (fold change = 2.11, P < 0.001), were verified using RT-qPCR. Among those, NR_038221, NR_003142, and ENST00000570366 were found to be up-regulated, while ENST00000422183 was down-regulated. The value of the area under the curve (AUC) for the diagnostic model consisting of the four lncRNAs was 0.845 (sensitivity = 79.2%, specificity = 75%). We further predicted 85 mRNAs and 404 miRNAs that potentially interact with these lncRNAs. Our study revealed the potential value of lncRNAs as biomarkers for early diagnosis of TB and the underlying mechanisms of these abnormally expressed lncRNAs in the pathogenesis of TB.

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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Figure 1
Figure 1
Differentially expressed lncRNAs and mRNAs between TB patients and healthy control subjects. (A–C) The Hierarchical Clustering Map, Scatter Plot and Volcano Plot of the differentially expressed lncRNAs, respectively. (D–F) The Hierarchical Clustering Map, Scatter Plot and Volcano Plot of the differentially expressed mRNAs, respectively.
Figure 2
Figure 2
GO and KEGG pathway analysis of differentially expressed mRNAs between TB patients and healthy control subjects. The most enriched GO items of the up-regulated mRNAs (A) and down-regulated mRNAs (B) according to biological process (BP), cellular components (CC) and molecular functions (MF). The most enriched items of the KEGG pathway analysis of the up-regulated mRNAs (C) and down-regulated mRNAs (D).
Figure 3
Figure 3
Part results of the CNC co-expression network. The yellow node represents the coding gene, the blue node represents lncRNAs, and the red node represents the verified lncRNAs. The solid line between the two nodes represents a positive correlation, and the dotted line represents a negative correlation. This figure showed that NR_038221 and ENST00000422183 had positive correlations with IL6ST and negative correlations with TLR6, NR_003142 had positive correlation with MT1H, and ENST00000570366 had positive correlations with CD3E and IL5.
Figure 4
Figure 4
The qRT-PCR validation of lncRNA expression levels in TB patients and healthy control subjects. Three lncRNAs were up-regulated in TB patients: NR_038221 (fold change = 3.79, P < 0.01), NR_003142 (fold change = 1.69, P < 0.05), and ENST00000570366 (fold change = 3.04, P < 0.05). ENST00000422183 (fold change = 2.11, P < 0.001) was down-regulated in TB patients compared with the healthy control subjects.
Figure 5
Figure 5
Receiver operating characteristic (ROC) curves analysis of the four lncRNAs. The AUC of the combination of four lncRNAs was 0.845 (95%CI, 0.742–0.949; P < 0.001, sensitivity = 79.2%, specificity = 75%). NR_038221 (0.677, 95%CI, 0.528–0.826; P = 0.029), NR_003142 (0.657, 95%CI, 0.503–0.811; P = 0.05), ENST00000570366 (0.672, 95%CI, 0.515–0.829; P = 0.034), and ENST00000422183 (0.738, 95%CI, 0.592–0.884; P = 0.003).
Figure 6
Figure 6
GO analysis of lncRNA-NR_038221 related to mRNAs according to the ceRNA analysis. (A) The GO items were enriched in regulation of transmembrane transport, detection of bacterium, MHC class II receptor activity, etc. (B) KEGG pathways enriched in Th1 and Th2 cell differentiation, tuberculosis and the Jak-STAT signalling pathway.
Figure 7
Figure 7
CeRNA analysis with lncRNA-NR_038221. 78 mRNAs and 368 miRNAs were associated with lncRNA-NR_038221. The blue node represents the coding gene, the red node represents miRNAs, and the green node represents the lncRNA-NR_038221.
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