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

TL;DR

This study shows that a genetic risk score based on four SNPs can predict unexplained recurrent miscarriages, especially in younger women and those with late miscarriages.

Contribution

A novel genetic risk score combining four platelet-related SNPs is proposed for predicting recurrent miscarriages.

Findings

Each additional polymorphic gene increased miscarriage risk with an odds ratio of 2.2.

The genetic risk score showed improved performance in younger patients with an AUC of 0.839.

Late miscarriage cases had a GRS AUC of 0.742 and an odds ratio of 3.6 per SNP.

Abstract

Background/Objectives: 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. Methods: 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. Results: 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, p < 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, p < 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, p < 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, p < 0.001) and an OR = 7.0 (95% CI: 2.8 to 17.8, p < 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, p = 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. Conclusions: 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.

Figures