MiR-146a rs2910164 (G/C) polymorphism is associated with the development and prognosis of acute coronary syndromes: an observational study including case control and validation cohort

Polymorphisms in microRNAs (miRNAs) play an important role in acute coronary syndromes (ACS). The purpose of this study was to assess the association of miR-146a rs2910164 and miR-34b rs4938723 polymorphisms with the development and prognosis of ACS and to explore the underlying mechanisms. A case-control study of 1171 subjects was included to determine the association of miR-146a rs2910164 and miR-34b rs4938723 polymorphisms with ACS risk. An additional 612 patients with different miR-146a rs2910164 genotypes, who underwent percutaneous coronary intervention (PCI) were included in the validation cohort and followed for 14 to 60 months. The endpoint was major adverse cardiovascular events (MACE). A luciferase reporter gene assay was used to validate the interaction of oxi-miR-146a(G) with the IKBA 3'UTR. Potential mechanisms were validated using immunoblotting and immunostaining. The miR-146a rs2910164 polymorphism was significantly associated with the risk of ACS (Dominant model: CG + GG vs. CC, OR = 1.270, 95% CI (1.000-1.613), P = 0.049; Recessive model: GG vs. CC + CG, OR = 1.402, 95% CI (1.017-1.934), P = 0.039). Serum inflammatory factor levels were higher in patients with the miR-146a rs2910164 G allele than in those with the C allele. MiR-146a rs2910164 polymorphism in dominant model was associated with the incidence of MACE in post-PCI patients (CG + GG vs. CC, HR = 1.405, 95% CI (1.018-1.939), P = 0.038). However, the miR-34b rs4938723 polymorphism was not associated with the prevalence and prognosis of ACS. The G allele of miR-146a rs2910164 tends to be oxidized in ACS patients. The miRNA fractions purified from monocytes isolated from ACS patients were recognized by the 8OHG antibody. Mispairing of Oxi-miR-146a(G) with the 3'UTR of IKBA results in decreased IκBα protein expression and activation of the NF-κB inflammatory pathway. P65 expression was higher in atherosclerotic plaques from patients carrying the miR-146a rs2910164 G allele. The variant of miR-146a rs2910164 is closely associated with the risk of ACS in Chinese Han population. Patients carrying miR-146a rs2910164 G allele may have worse pathological change and poorer post-PCI prognosis, partly due to the oxidatively modified miR-146a mispairing with 3'UTR of IKBA and activating NF-κB inflammatory pathways.