Genetic Polymorphisms in the 3'-Untranslated Regions of SMAD5, FN3KRP, and RUNX-1 Are Associated with Recurrent Pregnancy Loss

Abstract

Recurrent pregnancy loss (RPL) is typically defined as two or more consecutive pregnancy losses prior to 20 weeks of gestation. Although the causes of idiopathic RPL are not completely understood, vascular development and glucose concentration were reported to correlate with the pregnancy loss. The TGF-β signaling pathway which plays a significant role in pregnancy is activated by the interaction between high glucose and SMAD signaling and affects the vascular cells. SMAD5 and RUNX-1 are involved in the TGF-β signaling pathway and contribute to advanced glycation end products (AGEs) production and vascular development. FN3KRP, a newly described gene, is also associated with vascular diseases and suggested to relate to AGEs. Therefore, in the present study, we investigated associations between RPL risk and genetic polymorphisms of SMAD5, FN3KRP, and RUNX-1 in 388 women with RPL and 280 healthy control women of Korean ethnicity. Participants were genotyped using real-time polymerase chain reaction and restriction fragment length polymorphism assay to determine the frequency of SMAD5 rs10515478 C>G, FN3KRP rs1046875 G>A, and RUNX-1 rs15285 G>A polymorphisms. We found that women with RPL had lower likelihoods of the FN3KRP rs1046875 AA genotype (adjusted odds ratio (AOR), 0.553; p = 0.010) and recessive model (AOR, 0.631; p = 0.017). Furthermore, combination analysis showed that SMAD5 rs10515478 C>G and FN3KRP rs1046875 G>A mutant alleles were together associated with reduced RPL risk. These findings suggest that the FN3KRP rs1046875 G>A polymorphism has a significant role on the prevalence of RPL in Korean women. Considering that it is the first study indicating a significant association between FN3KRP and pregnancy disease, RPL, our results suggest the need for further investigation of the role of FN3KRP in pregnancy loss.

Keywords: FN3KRP; RUNX-1; SMAD5; polymorphism; recurrent pregnancy loss.

Figure 1

Overview of the formation and impact of AGEs. Proteins in the blood, such as albumin and hemoglobin, react with plasma glucose and generate glycated proteins including fructosamine and HbA1c, leading to the formation of AGEs through non-enzymatic glycation. The AGE formation process is restricted by FN3K, which is similar in structure to FN3KRP. The high level of AGEs can induce multiple diseases such as cancer, diabetes mellitus, vascular system dysfunction and infertility and interacts with the TGF- β signaling pathway. In our study, we indicated the association between FN3KRP rs1046875 G>A and RPL. Therefore, we propose that FN3KRP may inhibit the formation of AGEs and affect the RPL, infertility diseases.