Genetic Associations of ITGB3, FGG, GP1BA, PECAM1, and PEAR1 Polymorphisms and the Platelet Activation Pathway with Recurrent Pregnancy Loss in the Korean Population

Abstract

Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more pregnancy losses before 20 weeks of gestation. RPL is a common medical condition among reproductive-age women, with approximately 23 million cases reported annually worldwide. Up to 5% of pregnant women may experience two or more consecutive pregnancy losses. Previous studies have investigated risk factors for RPL, including maternal age, uterine pathology, genetic anomalies, infectious agents, endocrine disorders, thrombophilia, and immune dysfunction. However, RPL is a disease caused by a complex interaction of genetic factors, environmental factors (e.g., diet, lifestyle, and stress), epigenetic factors, and the immune system. In addition, due to the lack of research on genetics research related to RPL, the etiology remains unclear in up to 50% of cases. Platelets play a critical role in pregnancy maintenance. This study examined the associations of platelet receptor and ligand gene variants, including integrin subunit beta 3 (ITGB3) rs2317676 A > G, rs3809865 A > T; fibrinogen gamma chain (FGG) rs1049636 T > C, rs2066865 T > C; glycoprotein 1b subunit alpha (GP1BA) rs2243093 T > C, rs6065 C > T; platelet endothelial cell adhesion molecule 1 (PECAM1) rs2812 C > T; and platelet endothelial aggregation receptor 1 (PEAR1) rs822442 C > A, rs12137505 G > A, with RPL prevalence. In total, 389 RPL patients and 375 healthy controls (all Korean women) were enrolled. Genotyping of each single nucleotide polymorphism was performed using polymerase chain reaction-restriction fragment length polymorphism and the TaqMan genotyping assay. All samples were collected with approval from the Institutional Review Board at Bundang CHA Medical Center. The ITGB3 rs3809865 A > T genotype was strongly associated with RPL prevalence (pregnancy loss [PL] ≥ 2: adjusted odds ratio [AOR] = 2.505, 95% confidence interval [CI] = 1.262-4.969, p = 0.009; PL ≥ 3: AOR = 3.255, 95% CI = 1.551-6.830, p = 0.002; PL ≥ 4: AOR = 3.613, 95% CI = 1.403-9.307, p = 0.008). The FGG rs1049636 T > C polymorphism was associated with a decreased risk in women who had three or more pregnancy losses (PL ≥ 3: AOR = 0.673, 95% CI = 0.460-0.987, p = 0.043; PL ≥ 4: AOR = 0.556, 95% CI = 0.310-0.997, p = 0.049). These findings indicate significant associations of the ITGB3 rs3809865 A > T and FGG rs1049636 T > C polymorphisms with RPL, suggesting that platelet function influences RPL in Korean women.

Keywords: allele combination; genotype combination; platelet activation; recurrent pregnancy loss; single-nucleotide polymorphism.

Figure 1

Graphical summary of platelet receptors and ligands investigated in this study.

Figure 2

Association between differences in white blood cell levels; the proportions of CD19⁺ B and CD56⁺ NK cells; and the FGG rs1049636 T > C and PEAR1 rs12137505 G > A polymorphisms in patients with recurrent pregnancy loss (RPL). (A) Association between CD19⁺ B cell proportions and the FGG rs1049636 T > C polymorphism. (B) Association between CD56⁺ NK cell proportions and the PEAR1 rs12137505 G > A in patients with RPL.

Figure 3

Synergic effect analysis for the interplay between TSH level and ITGB3 rs3809865 A > T gene polymorphism in RPL prevalence. (A) Categorized TSH levels into two groups: < 2.5 μU/mL and ≥ 2.5 μU/mL. (B) Divided TSH levels into quartiles.