A Circulating MicroRNA Signature Serves as a Diagnostic and Prognostic Indicator in Sarcoidosis

Abstract

Micro-RNAs (miRNAs) act as post-transcriptional regulators of gene expression. In sarcoidosis, aberrant miRNA expression may enhance immune responses mounted against an unknown antigenic agent. We tested whether a distinct miRNA signature functions as a diagnostic biomarker and explored its role as an immune modulator in sarcoidosis. Expression of miRNAs from peripheral blood mononuclear cells from subjects that met clinical and histopathologic criteria for sarcoidosis were compared to those from matched controls in the ACCESS study. Signature miRNAs were determined by miRNA microarray analysis and validated by quantitative reverse transcription PCR (RT-qPCR). Microarray analysis identified 54 differentially expressed feature mature human miRNAs between groups. Significant feature miRNAs that distinguish sarcoidosis from controls were selected by use of probabilistic models adjusted for clinical variables. Eight signature miRNAs were chosen to verify the diagnosis of sarcoidosis in a validation cohort and distinguished sarcoidosis from controls with a positive predictive value of 88%. We identified both novel and previously described genes and molecular pathways associated with sarcoidosis as targets of these signature miRNAs. Additionally, we demonstrate that signature miRNAs (hsa-miR-150-3p and hsa-miR-342-5p) are significantly associated with reduced lymphocytes and airflow limitations, known markers of poor prognosis. Together, these findings suggest that a circulating miRNA signature serves as a non-invasive biomarker that supports the diagnosis of sarcoidosis. Future studies will test the miRNA signature as a prognostication tool associated with poor clinical outcomes in sarcoidosis.

Expression analysis of extracellular microRNA in bronchoalveolar lavage fluid from patients with pulmonary sarcoidosis

“…Eight published reports so far have investigated miRNA expression in pulmonary sarcoidosis, but none addressed miRNA encapsulated in EV from the lung and all were limited to cellular expression in blood cells, bronchoalveolar cells and serum; some of these studies, however, provided contradictory results. While some of the previous findings in BAL cells may complement our present observations, the EV/exosomal miRNA remained unexplored in these investigations.…”

“…8 The differential miRNA expression in extracellular and cellular components has raised the possibility that they display distinct functions at the compartmental level, and thus, could be potential candidate signatures for biological processes such as cellular activation and differentiation. 13 The presence of circulating extracellular miRNA with proinflammatory roles has been reported in various lung diseases 1,8,10,12,14,15 and it has been suggested they may serve as potential biomarkers due to their higher stability. These stable miRNA are packaged and transported during cellular communications in extracellular vesicles (EV), namely exosomes (size: 30-100 nm; endosomal origin) and microvesicles (MV) (>100-1000 nm; plasma membrane origin), that protect them against any enzymatic/RNase degradation.…”

“…Sarcoidosis is a multisystemic granulomatous disorder of unknown aetiology that mainly affects the lungs. Small non‐coding microRNA (miRNA) are transcriptional regulators and their plausible pro‐inflammatory role in pulmonary sarcoidosis has been suggested . Most studies have investigated the transcription profile of cellular miRNA at the systemic level (peripheral blood cells) .…”

“…Small non‐coding microRNA (miRNA) are transcriptional regulators and their plausible pro‐inflammatory role in pulmonary sarcoidosis has been suggested . Most studies have investigated the transcription profile of cellular miRNA at the systemic level (peripheral blood cells) . The association of dysregulated miRNA in bronchoalveolar lavage (BAL) cells and serum from patients with sarcoidosis, its clinical course and its subgroups compared with controls have also been reported .…”

“…[1][2][3][4][5][6][7][8] Most studies have investigated the transcription profile of cellular miRNA at the systemic level (peripheral blood cells). [1][2][3][4][5] The association of dysregulated miRNA in bronchoalveolar lavage (BAL) cells and serum from patients with sarcoidosis, its clinical course and its subgroups compared with controls have also been reported. [5][6][7][8] These miRNA are present not only in cellular but also in extracellular compartments.…”