Genetic Association between Inflammatory-Related Polymorphism in STAT3, IL-1β, IL-6, TNF-α and Idiopathic Recurrent Implantation Failure

Abstract

Recurrent implantation failure (RIF) is defined as a failure to achieve pregnancy after multiple embryo transfers. Implantation is closely related to inflammatory gradients, and interleukin-1beta (IL-1β), IL-6, and tumor necrosis factor-alpha (TNF-α) play a key role in maternal and trophoblast inflammation during implantation. Signal transducer and activator of transcription 3 (STAT3) interacts with cytokines and plays a critical role in implantation through involvement in the inflammation of the embryo and placenta. Therefore, we investigated 151 RIF patients and 321 healthy controls in Korea and analyzed the association between the polymorphisms (STAT3 rs1053004, IL-1β rs16944, IL-6 rs1800796, and TNF-α rs1800629, 1800630) and RIF prevalence. In this paper, we identified that STAT3 rs1053004 (AG, adjusted odds rate [AOR] = 0.623; p = 0.027; GG, AOR = 0.513; p = 0.043; Dominant, AOR = 0.601, p = 0.011), IL-6 rs1800796 (GG, AOR = 2.472; p = 0.032; Recessive, AOR = 2.374, p = 0.037), and TNF-α rs1800629 (GA, AOR = 2.127, p = 0.010, Dominant, AOR = 2.198, p = 0.007) have a significant association with RIF prevalence. This study is the first to investigate the association of each polymorphism with RIF prevalence in Korea and to compare their effect based on their function on inflammation.

Genetic Correlation of miRNA Polymorphisms and STAT3 Signaling Pathway with Recurrent Implantation Failure in the Korean Population

“…Consistent with previous research regarding the role of STAT3 in the prevalence of RIF, our findings align with a growing body of evidence indicating that individuals with the miR-34a rs3577555 G>A AA genotype are at a higher risk for RIF compared to those with other genotypes [18]. This observation corroborates results from previous studies involving various cell types, where the introduction of miR-34a was shown to reduce STAT3 phosphorylation by directly targeting the mRNA of interleukin 6 receptor (IL-6R) [15,26].…”

“…Through previous studies examining the impact of various SNPs, it has become evident that genetic variants significantly influence the prevalence and prognosis of RIF [18][19][20][21]. Recent findings have also established connections between genetic variations and inflammation in susceptibility to RIF [22].…”

“…Our previous investigations revealed that specific SNPs in genes associated with inflammation can substantially modify gene expression, thus profoundly affecting susceptibility to RIF [18]. Here, our primary focus was to examine the correlation between miRNA SNPs impacting STAT3 and the likelihood of developing RIF.…”

“…In summary, our study revealed a strong association between the miR-34a rs6577555 C>A SNP and the risk of RIF in Korean women, particularly concerning the number of IFs. Given STAT3's involvement in both inflammation and implantation [18], we conducted a comprehensive analysis to examine the intricate relationship between miRNA SNPs (miR-218-2 rs11134527 G>A, miR-34a rs2666433 G>A, miR-34a rs6577555 C>A, and miR-130a rs731384 G>A) and their impact on STAT3 gene expression, thereby influencing patient susceptibility to RIF.…”

Absence of Heme Oxygenase-1 Affects Trophoblastic Spheroid Implantation and Provokes Dysregulation of Stress and Angiogenesis Gene Expression in the Uterus

“…Il27 , correlated with an immune–inflammatory imbalance in the pre-term [ 42 ], showed increased expression in Hmox1 −/− uteruses. Similarly, the upregulation of Il11 , was previously associated with inflammation and pre-eclampsia features in mice [ 43 ] and Il1b , linked to idiopathic recurrent implantation failure [ 44 ], indicated a pro-inflammatory milieu.…”