Circulating Long Noncoding RNAs Positively Correlate with the Increased Risk, Elevated Severity and Unfavorable Prognosis in the Sepsis Patients
Authors: Yuan Jun , Cao Limian , Bao Junjie , Zha Yutao , Chen Shi , Fan Wenjing , Fang Ming , Gui Yonghui , Liu Nian , Shao Min 
Published: January 2022

Abstract
Objective

This study aimed to evaluate the correlation of circulating long noncoding RNAs (lncRNAs) expression with disease risk, severity, inflammatory cytokines levels and prognosis in patients with sepsis.
Methods

Differential expression profiles of lncRNA in the serum of sepsis rats were screened by high-throughput transcriptome sequencing. Homologous lncRNAs in the upregulation group were identified by homology analysis in rats and humans. The expression differences of these homologous lncRNAs in the serum of 176 sepsis patients and 176 healthy controls (HCs) were detected using reverse transcription quantitative polymerase chain reaction (RT-qPCR). And inflammatory cytokines levels were detected by enzyme-linked immunosorbent assay (ELISA). A receiver operating characteristic (ROC) curve was used to verify the diagnostic and prognosis values. Spearman correlation coefficient was used to analyze the correlation between the variables. Follow-up was performed to observe the 28-day mortality.
Results

Among the screened differentially up-regulated lncRNAs, only two lncRNAs were homologous in rats and humans, which in human named PKN2-antisense RNA 1 (PKN2-AS1) and AC068888.1, respectively. Those two lncRNAs were significantly increased in patients with sepsis compared with those in HCs (P < 0.001), in patients with septic shock compared with those no septic shock (P < 0.001), and in non-survivors compared with survivors (P < 0.001). And those two lncRNAs were positively correlated with sepsis-related organ failure assessment (SOFA) score, acute physiology and chronic health evaluation (APACHE) II score, lactate (Lac), c-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) in sepsis patients. Likelihood ratio forward stepwise multivariate logistic regression analysis revealed that high lncRNA AC068888.1 expression was an independent risk factor for septic shock (P < 0.001) and unfavorable prognosis (P = 0.006), but high lncRNA PKN2-AS1 expression was only for unfavorable prognosis (P = 0.019). The ROC curve exhibited a significant predictive value for sepsis risk with area under the curve (AUC) values of 0.879 and 0.842, respectively. For predicting septic shock risk, combining lncRNA AC068888.1 with SOFA score and Lac level, the ROC curve analysis significantly improved the predictability (AUC = 0.882). For predicting 28-day death risk, combining those two lncRNAs with SOFA and APACHE II scores, the ROC curve analysis also significantly improved the predictability (AUC = 0.860). The Kaplan–Meier curves indicated that the survival probability was much worse with those two lncRNAs high expression compared to low expression in patients with sepsis (P < 0.001).
Conclusion

The circulating absolute expression levels of lncRNA PKN2-AS1 and AC068888.1 in the serum may be used for the early diagnosis, clinical severity evaluation and prognosis of sepsis.