A Genetic Risk Score for Recurrent Miscarriages Based on Polymorphisms in Platelet Glycoproteins and Adhesion Molecules Genes

<b>Background/Objectives:</b> The objective of the study was to explore the combined effect of polymorphisms in the platelet glycoproteins Ia (GpIa) and IIIa (GpIIIa), along with the platelet-endothelial cell adhesion molecule-1 (PECAM-1) and P-Selectin genes, on the risk of recurrent pregnancy loss. <b>Methods:</b> This study involved 162 women with primary unexplained recurrent miscarriages and 60 fertile controls who had at least one uncomplicated full-term pregnancy without experiencing fetal loss. All participants were of Greek origin and were genotyped for four single nucleotide polymorphisms (SNPs), GpIa-C807T, GpIIIa-PlA1/PlA2, PECAM-1-C373G, and P-Selectin-A37674C, using pyrosequencing. A genetic risk score (GRS) was calculated in two forms: one based on the number of SNPs (dominant model) and the other based on the number of polymorphic alleles (additive model), utilizing logistic regression and receiver operator characteristic (ROC) analyses. <b>Results:</b> A statistically significant increase in the risk of miscarriage was observed with the number of polymorphic genes, with an odds ratio (OR) of 2.2 (95% confidence interval [CI]: 1.5 to 3.2, <i>p</i> < 0.001) for each additional SNP. The ROC analysis revealed an area under the curve (AUC) of 0.689 (95% CI: 0.614 to 0.763, <i>p</i> < 0.001). The presence of two or more polymorphic genes demonstrated a sensitivity of 69.8% and specificity of 65%, with an OR = 4.3 (95% CI: 2.3 to 8.0, <i>p</i> < 0.001). The performance of the GRS improved in younger patients and those experiencing late miscarriages. An AUC = 0.839 (95% CI: 0.749 to 0.930, <i>p</i> < 0.001) and an OR = 7.0 (95% CI: 2.8 to 17.8, <i>p</i> < 0.001) per SNP were achieved for the age group < 30 years. For subjects with second trimester fetal loss, the GRS yielded an AUC = 0.742 (95% CI: 0.610 to 0.874, <i>p</i> = 0.002) and an OR = 3.6 (95%OR = 7.0, 95% CI: 2.8 to 17.8) per SNP. The allelic GRS produced similar or slightly diminished results. <b>Conclusions:</b> This study highlights the promising potential of a genetic risk score based on four SNPs in predicting unexplained recurrent miscarriages, particularly in younger individuals and in cases of late miscarriage. These findings contribute to a deeper understanding of the epidemiology of unexplained recurrent miscarriage, emphasizing the role of platelet thrombophilia.