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MINI: Circulating microRNAs provide an insight into current disease states. Comparing patients with degenerative disc disease to healthy controls, patients with disc disease were found to have significantly downregulated levels of miR-155-5p. This marker was found to be an accurate diagnostic predictor for the presence of degeneration (P = 0.006). STUDY DESIGN Case-control study measuring differential gene expression of circulating microRNA (miRNA) in patients with degenerative disc disease (DDD). OBJECTIVE To identify miRNA dysregulation in serum samples of patients with DDD compared to healthy controls (HC). SUMMARY OF BACKGROUND DATA Early DDD can be a difficult diagnosis to make clinically, with lack of positive and specific findings on physical exam or advanced imaging. miRNAs are a class of molecules that act as gene regulators and have been shown to be dysregulated in local degenerative disc tissue. However, to date no studies have identified dysregulation of serum miRNA in patients with DDD. METHODS Whole blood samples were obtained from 69 patients with DDD and 16 HC. Patient-reported outcomes were collected preoperatively and degree of DDD was classified using Pfirrmann grade on preoperative imaging. Differential gene expression analysis using a screening assay for several hundred miRNAs and further characterization for five specific miRNAs (miR-16-5p, miR-21-5p, miR-142-3p, miR-146a-5p, and miR-155-5p) was performed. In addition, a pro-inflammatory cytokine multiplex assay and bioinformatics analysis were done. RESULTS The initial screening assay showed 13 miRNA molecules that were significantly dysregulated in DDD patients, with miR-155-5p showing significant downregulation (p = 0.027) and direct interactions with the pro-inflammatory cytokine IL-1β, and the tumor suppressor genes p53 and BRAF. Analyzing the whole cohort, miR-155 showed an almost four-fold downregulation in DDD patients (-3.94-fold, P < 0.001) and was the sole miRNA that accurately predicted the presence of disc degeneration (P = 0.006). Downregulation of miR-155 also correlated with increased leg pain (P = 0.018), DDD (P = 0.006), and higher Pfirrmann grade (P = 0.039). On cytokine analysis, TNF-α (0.025) and IL-6 (P < 0.001) were significantly higher in DDD patients. CONCLUSION Serum miR-155-5p is significantly downregulated in patients with DDD and may be a diagnostic marker for degenerative spinal disease. LEVEL OF EVIDENCE N/A.