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

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 (<i>ITGB3</i>) rs2317676 A > G, rs3809865 A > T; fibrinogen gamma chain (<i>FGG</i>) rs1049636 T > C, rs2066865 T > C; glycoprotein 1b subunit alpha (<i>GP1BA</i>) rs2243093 T > C, rs6065 C > T; platelet endothelial cell adhesion molecule 1 (<i>PECAM1</i>) rs2812 C > T; and platelet endothelial aggregation receptor 1 (<i>PEAR1</i>) 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 <i>ITGB3</i> 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, <i>p</i> = 0.009; PL ≥ 3: AOR = 3.255, 95% CI = 1.551-6.830, <i>p</i> = 0.002; PL ≥ 4: AOR = 3.613, 95% CI = 1.403-9.307, <i>p</i> = 0.008). The <i>FGG</i> 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, <i>p</i> = 0.043; PL ≥ 4: AOR = 0.556, 95% CI = 0.310-0.997, <i>p</i> = 0.049). These findings indicate significant associations of the <i>ITGB3</i> rs3809865 A > T and <i>FGG</i> rs1049636 T > C polymorphisms with RPL, suggesting that platelet function influences RPL in Korean women.