Subclinical atherosclerosis in rheumatoid arthritis is driven by MicroRNA polymorphisms and NETosis

BACKGROUND: Rheumatoid arthritis (RA) is associated with increased cardiovascular disease (CVD) risk, not fully explained by traditional risk factors. Neutrophil extracellular traps (NETs) and regulatory microRNA polymorphisms (miR-SNPs) may contribute to RA-related atherosclerosis through thromboinflammatory mechanisms. OBJECTIVES: To investigate whether miR-SNPs (rs2431697, rs3746444, rs11614913) are associated with subclinical atherosclerosis in RA, and whether NETosis mediates this relationship. METHODS: We genotyped 620 RA patients and 359 healthy controls. Carotid intima-media thickness (CIMT) was assessed in 65 RA patients and 75 controls. Circulating NETosis markers (cfDNA and citH3–DNA) were quantified. Logistic regression models evaluated the association between miR-SNPs and pathological CIMT (pCIMT), accounting for RA status and cardiovascular risk factors. RESULTS: The rs11614913 C allele was associated with RA susceptibility. pCIMT was significantly more frequent in RA patients than in controls (75.4% vs. 45.3%, p < 0.001). RA-specific associations were observed between pCIMT and both rs2431697 and rs3746444. The rs2431697 T allele was also associated with increased citH3–DNA levels, suggesting enhanced NETosis. CONCLUSIONS: miR-SNPs rs2431697 and rs3746444 are associated with subclinical atherosclerosis in RA and, in the case of rs2431697, preliminary results suggest that NETosis could be an underlying mechanism. These findings support their potential as biomarkers and therapeutic targets to reduce CVD risk in RA.