Two epigenetic markers of the fibromyalgia syndrome: A matched case-control study

MicroRNAs (miRs) are involved in regulating various biological processes and may contribute to the pathophysiology of fibromyalgia syndrome (FMS). In order to explore correlations with clinical characteristics and to identify specific clusters, we performed plasma miR sequencing in 113 FMS patients diagnosed on ACR 2016 criteria and in 29 healthy volunteers (HV). All FMS patients were women, an important point as sex differences in FMS and immune regulation are well-documented. Subgrouping of FMS patients identified two distinct molecular clusters (FM1 and FM2), with FM1 showing significant miR dysregulation, compared to HV. Clinically, FM1 and FM2 did not differ in terms of age, disease severity, pain score, or quality of life. In parallel, the miRs analysis of clinical clusters ("severe", "intermediate" and "mild" FM) showed two significantly dysregulated miRs: miR-4771 and miR-2115-3p, and both correlated with the "impact on functioning" score of the Brief Pain Inventory questionnaire. Bioinformatics analysis suggested that both miRs may be involved in the TGF-β signalling pathway, potentially linking neuroimmune dysregulation with symptom severity. Given that this study focuses on women patients, future research should address whether these findings are applicable to men or in mixed-sex populations, which could enhance the generalizability of the results. This study highlights the epigenetic heterogeneity of FMS, and suggests that two miRs could serve as potential biomarkers for disease stratification, and targets for personalized therapies. Future studies are needed to validate these findings and to explore their clinical potential. PERSPECTIVE: Using high-throughput sequencing of plasma miRNAs, this study identifies two miRs associated with FMS severity and reveals distinct molecular subgroups. These findings highlight the biological heterogeneity of FMS and may inform future biomarker-based approaches to diagnosis and therapy.