Expression analysis of Long Non-Coding RNAs in systemic lupus erythematosus

Abstract

 Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease with heterogeneous clinical manifestations. It is mainly caused by a breakdown of self-tolerance and production of autoantibodies under the predisposition of genetic and environmental factors. Long non-coding RNAs (lncRNAs) recently emerge as important transcriptional and translational regulators of many cellular activities. Some lncRNAs have been shown to be involved in normal physiological regulation as well as in pathological conditions including SLE. LncRNAs are involved in disease pathogenesis and can serve as potential biomarkers. However, the current understanding on the involvement of lncRNAs in SLE is still limited. Therefore, this study aimed at identifying novel lncRNAs that are associated with SLE. Their potential involvement in the disease pathogenesis was also evaluated. Five differentially expressed lncRNA targets including LINC01268, LINC02207, AL035661.1, RP11-196G18.24 and AC012368.2, and five differentially expressed cytokine/chemokine-related mRNA were identified by comparing the blood transcriptome of SLE patients with or without lupus nephritis in a pilot study. The expression of these lncRNAs were validated in an independent patient cohort and further compared between SLE patients and healthy controls. Results showed that three of the lncRNAs, including LINC02207, RP11-196G18.24 and AC012368.2 were upregulated in total leukocytes of SLE patients. The expression of IL18RAP and IL1R1 were also upregulated in SLE total leukocytes while IL-18 and CCR4 were downregulated. The expression of LINC02207 in total leukocytes was positively correlated with the expression of IL18RAP, IL18R1 and IL1R1 and negatively correlated with the expression of CCR4. The expression of RP11-196G18.24 and AC012368.2 were both positively correlated with the expression of IL18RAP, IL18R1 and IL1R1. LINC02207 had the highest differential expression among the three lncRNAs and leukocyte subset analysis revealed that it was mainly expressed in neutrophils. Further studies showed that LINC02207 was upregulated in SLE neutrophils, and its expression was positively correlated with the expression of IL18RAP, IL18R1, IL-18 and IL1R1. Receiver operator characteristics (ROC) analysis of lncRNA targets in total leukocytes and LINC02207 in neutrophils were done. LINC02207, RP11-196G18.24 and AC012368.2 in total leukocytes showed an area under curve (AUC) of 0.85 [0.74, 0.96], 0.66 [0.51, 0.82] and 0.72 [0.59, 0.96] respectively, while LINC02207 in neutrophils had an AUC of 0.87 [0.75, 1.00]. In conclusion, the result suggests that LINC02207 is potentially involved in the functional regulation of the expression of IL-18, IL-18 receptors and IL-1 receptor in neutrophils. Further investigations on the functional role of this lncRNA in neutrophils are needed. Whether this lncRNA may participate in the pathogenesis of SLE warrants further investigations.