Association of miRNA (miR-10a, miR-30c, miR-181a, and miR-499b) Polymorphisms and Their Interactions with PAI-1 in Recurrent Implantation Failure in Korean Women.

Abstract

Recurrent implantation failure (RIF) remains a major challenge in assisted reproductive technology, and accumulating evidence suggests that genetic factors, including microRNA (miRNA) polymorphisms, may influence implantation outcomes. This study investigated the association between RIF and polymorphisms in miR-10a A > T, miR-30c A > G, miR-181a T > C, and miR-499b A > G in Korean women. Peripheral blood samples were obtained from 169 women with RIF and 281 fertile controls, and genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism and real-time polymerase chain reaction. While individual miRNA polymorphisms were not independently associated with RIF in the overall population, subgroup analyses revealed that the miR-499b AG genotype was significantly associated with increased risk in women with ≥ 4 implantation failures (AOR = 1.908, P = 0.021). Stratified analysis showed that the miR-181a TC + CC genotype increased RIF risk in women with lower platelet counts, whereas the miR-30c AG + GG genotype consistently exerted a protective effect, particularly in subjects with a BMI ≥ 25 kg/m² (AOR = 0.104, P = 0.012) and those with shorter aPTT (AOR = 0.216, P = 0.002). Since plasminogen activator inhibitor-1 (PAI-1) is a confirmed (miR-10a, -30c, -181a) or predicted (miR-499b) target of these miRNAs, we further investigated the interactions between these miRNA polymorphisms and PAI-1, a key gene in implantation. Significant synergistic effects were observed between PAI-1 and miRNA polymorphisms. The A-T-C combination of PAI-1/miR-181a was strongly associated with susceptibility (OR = 2.644, P = 0.002, FDR-p = 0.014). Conversely, the G-T-G (PAI-1/miR-30c) combination was found exclusively in controls, indicating a protective effect (OR = 0.055, P = 0.002, FDR-p = 0.014). Furthermore, certain multilocus allele combinations involving PAI-1 showed potential associations with RIF risk, although estimates for rare combinations had wide confidence intervals and should be interpreted cautiously. Conclusion: These findings suggest that miRNA- and PAI-1-related genetic variation may contribute to RIF susceptibility in Korean women; however, several multilocus findings were exploratory and require validation in larger cohorts.