Mendelian randomization reveals the causal links between miRNAs and rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent joint inflammation and progressive structural damage, with early diagnosis remaining a significant clinical challenge. Circulating microRNAs (miRNAs) have emerged as promising biomarkers for disease diagnosis, prognosis, and therapeutic response due to their critical roles in gene regulation. However, the specific miRNAs causally involved in RA pathogenesis remain largely unidentified. We conducted a 2-sample Mendelian randomization (MR) analysis using summary-level data from the largest available genome-wide association study of circulating cis-miRNA expression quantitative trait loci (cis-miR-eQTLs) and RA genome-wide association study summary statistics. The inverse variance weighted method served as the primary analytical approach, supplemented by comprehensive sensitivity analyses including Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out analysis to ensure result robustness. Additionally, we performed target gene prediction, gene ontology and kyoto encyclopedia of genes and genomes enrichment analyses, and druggable analysis to explore the underlying biological mechanisms and therapeutic potential of the causal miRNAs. Our MR analysis identified 8 circulating miRNAs with significant causal associations with RA risk. Notably, hsa-miR-130a-3p (P = 6.5332 × 10-5, OR = 1.0720, 95% CI = 1.0360-1.1092) emerged as a key risk factor, while hsa-miR-204-5p (P = 6.2123 × 10-4, OR = 0.9707, 95% CI = 0.9543-0.9874) demonstrated a protective effect. Bioinformatics analyses revealed that hsa-miR-130a-3p may modulate the TGF-β, Hippo, and mTOR signaling pathways by interacting with competing endogenous RNAs (ceRNAs) such as H19 and regulating hub proteins including TNF, UBB, PPARG, and TGFBR1. Resveratrol and flufenamic acid were identified as candidate therapeutic agents targeting its downstream pathways. Conversely, hsa-miR-204-5p was predicted to influence the AMPK, cGMP-PKG, and cAMP signaling pathways via ceRNAs like NEAT1 and NORAD, affecting key proteins such as BCL2, SIRT1, and HMGA2, with cilostazol, melatonin, and curcumin identified as potential modulators. This study provides novel causal evidence implicating hsa-miR-130a-3p and hsa-miR-204-5p in RA pathogenesis. These findings highlight their potential as circulating biomarkers for early diagnosis and risk assessment, as well as therapeutic targets for miRNA-based intervention strategies, thereby offering valuable insights for advancing precision medicine in RA management.