Research Article: Diagnostic significance of circulating miRNAs in systemic lupus erythematosus

Date Published: June 4, 2019

Publisher: Public Library of Science

Author(s): Xiaolan Zheng, Yi Zhang, Peng Yue, Lei Liu, Chuan Wang, Kaiyu Zhou, Yimin Hua, Gang Wu, Yifei Li, Ronpichai Chokesuwattanaskul.

http://doi.org/10.1371/journal.pone.0217523

Abstract

In recent years, many studies focused on the association between the microRNAs (miRNAs) and the risk of systemic lupus erythematosus (SLE), especially miRNA-21 (miR-21). We aimed to investigate the role of circulating miRNAs, especially the miR-21, as a biomarker in detecting SLE.

We searched PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, and China National Knowledge Infrastructure through Mar 3th, 2019. We performed this meta-analysis in a fixed/random-effect model using Meta-disc 1.4 and STATA 15.1.

A total of 17 relevant studies were eligible to analyze pooled accuracy. The overall performance of total mixed miRNAs (TmiRs) detection was: pooled sensitivity, 0.71 (95% confidence interval [CI], 0.69 to 0.72); pooled specificity, 0.81 (95%CI, 0.79 to 0.83); and area under the summary receiver operating characteristic curves value (SROC), 0.8797. The miR-21 detection was: pooled sensitivity, 0.68 (95%CI, 0.62 to 0.74); pooled specificity, 0.77 (95%CI, 0.69 to 0.84); and SROC, 0.8281. The meta-regression analysis showed that the type of samples was the sources of heterogeneity. The subgroup analysis suggested that detection in plasma group had the largest AUC of SROC in all the subgroups: pooled sensitivity, 0.8 (95%CI, 0.78 to 0.82); pooled specificity, 0.83 (95%CI, 0.8 to 0.86); and SROC, 0.9068.

Our meta-analysis demonstrated that circulating miRNAs might be potential novel biomarkers for detecting SLE, especially miR-21. Moreover, plasma is recommended as the clinical specimen for diagnostic detection.

Partial Text

Systemic lupus erythematosus (SLE) is a complex, chronic, potentially fatal, multisystem autoimmune disease, which predominantly affects women between puberty and menopause [1]. The major pathogenetic mechanisms of SLE include an inappropriate immune response to the nucleic acid containing cellular particles, which is caused by an autoimmune reaction of the innate and adaptive immune systems, leading to damage structures of the skin, joints, kidney and central nervous system [2, 3]. Mortality in SLE patients has improved over the past 30 years but remains considerably higher than in people from the same geographical area without SLE [4]. Delay in diagnosis is associated with increased damage to vital organs [5]. In clinical practice, the diagnosis of SLE is mainly according to the revised American College of Rheumatology (ACR) classification criteria, which is made based on clinical manifestations and laboratory tests [6]. Laboratory tests, such as Complement (C3, C4), and antibodies (ANA, dsDNA, ACL, etc.) have although been demonstrated have potential as SLE diagnostic biomarkers, but none of them can accurately diagnose SLE [7–10]. The diagnosis of SLE is very challenging because there are no generally accepted diagnostic criteria [2]. Therefore, it is important to find novel and reliable circulating biomarkers for the diagnosis of SLE.

Since the introduction of miRNAs almost a decade ago, a series of publications have demonstrated the emerging role of miRNAs in the regulation of immune system development, maturation, and the pathological mechanisms of autoimmune disease, including SLE [43–47]. Furthermore, they can also be used in monitoring SLE disease severity function as novel potential targets for lupus treatment [47]. Meanwhile, many investigations had been carried out to assess whether miRNAs have sufficient capability to be used as biomarkers for SLE [48–50]. In this meta-analysis, we enrolled 17 studies and finally found that TmiRs achieved a combined AUC of 0.8797 with 71% pooled sensitivity, and 81% pooled specificity, which indicated that miRNAs had a moderate diagnostic accuracy as a diagnostic biomarker in discriminating SLE from healthy people. Furthermore, we examined single individual miRNAs among the total miRNA library and found that miR-21 was the most repeatedly used in individual studies recently. Based on this, we enrolled five studies on miR-21 and found a summary sensitivity of 0.68 (95%CI, 0.62 to 0.74) and summary specificity of 0.77 (95%CI, 0.69 to 0.84). In addition, the AUC value reached 0.8281±0.0608, which suggested that miR-21 had a moderate diagnostic accuracy in detecting SLE. Moreover, we also pooled the results of TmiRs after excluding the five studies on miR-21 for further confirmation. Although the AUC value rose slightly to 0.8895±0.0152 compared to that of TmiR, it still couldn’t deny the advantages of miR-21 in detecting SLE. To our knowledge, this is the first meta-analysis that focused on the accuracy of miR-21 in detecting SLE and confirmed the diagnostic accuracy of miRNAs as potential biomarkers for SLE.

As some pooled results showed large heterogeneities, several limitations of this meta-analysis need to be addressed. First, our meta-analysis included 39 miRNA markers, with only six miRNA markers that were repeatedly identified in two or three of the included publications except for miR-21, so that we did not conduct a meta-analysis on the same individual miRNA markers across publications except for miR-21. Second, due to the lack of conventional methodologies for an accurate absolute quantification of miRNAs, which limits the cross-comparison between studies performed by different laboratories, might produce unconvincing results for the included studies. Third, no included articles combine miRNAs with other laboratory tests, such as complement and antibodies to identify the diagnostic accuracy of SLE, which could work as a better method for detection. Besides, the times of sample obtained were varied among included studies, which might generated bias and decrease the strength in interpreting the results.

In conclusion, despite these limitations, our meta-analysis demonstrated that circulating miRNAs might be potential novel biomarkers for detecting SLE, especially miR-21. Moreover, plasma is recommended as the clinical specimen for diagnostic detection. Therefore, more well-designed researches need to be done to launch the application of miRNAs as biomarkers for SLE detection in the clinic. Furthermore, a combination of miRNAs and other laboratory tests needs to be worked as a better method for detection.

 

Source:

http://doi.org/10.1371/journal.pone.0217523