P-498 Towards precision medicine: maternal genetic profiles as determinant of adequate decidualization and reproductive success; a prospective study in oocyte donation cycles.
Authors: Cuadrado Torroglosa I , Pareja S , Balas A , García-Velasco J A , Alecsandru D 
Published: June 2023

Abstract

Study question
To determine the impact of genes related to decidualization and immune cell activation as predictors for reproductive success.

Summary answer
Women with unfavorable genetic profiles for Human Leukocyte Antigen (HLA)-F and Killer Immunoglobulin-like Receptor (KIR) genes showed decreased pregnancy rates.

What is known already
KIR genes encode receptors present on uterine Natural Killer (uNK) cells that are essential during placentation and early gestation. It has been established that women of KIR AA genotype show lower reproductive success than KIR BX, due to the lack of activation of these immune cells. Additionally, another gene, HLA-F, expressed in endometrial cells, also seems to be involved in the recruitment and supplementary activation of uNKs. Certain alleles of this gene appear to decrease its expression in the uterus and hinder the processes in which it is involved during the decidualization process, decreasing implantation rates and increasing time-to-pregnancy.

Study design, size, duration
We conducted a prospective cohort study with 75 patients, with no history of recurrent miscarriage or implantation failure, who attended our institution to undergo assisted reproduction treatments (ART) with donated oocytes, between January 2021 and December 2022. By using the egg donation model, we were able to investigate the endometrial cell population avoiding the oocyte factor bias

Participants/materials, setting, methods
All patients included were under 45 years of age (40.5 ± 2.9 years), had a normal BMI (21.6 ± 1.9 kg/m2) and had not been diagnosed with uterine pathologies or immunological conditions. All recipients were genotyped for the KIR and HLA-F genes and pregnancy, miscarriage (MR) and live birth rates (LBR) obtained in their egg donation cycles were recorded. Fisher's test was used to determine statistically significant differences (p &lt; 0.05) between groups

Main results and the role of chance
Patients were divided into two groups according to their KIR genotype: 29 KIR AA (inhibitor) and 46 KIR BX (activator). In each group, allelic load was determined for the three HLA-F regions studied (RS1362126, RS2523405 and RS2523393). For all these regions, patients with favorable HLA-F alleles and KIR BX genotype had higher pregnancy rates than KIR AA patients with unfavorable HLA-F alleles (85.42 % vs 54.17% for RS1362126 region, OR = 4.956, p = 0.008; 83.33% vs 58.62% for RS2523405 region, OR = 3.529, p = 0.0295; 82.5% vs 57.69% for RS2523393 region, OR = 3.457, p = 0.0462). No significant differences were obtained for MR or LBR. This demonstrates the involvement of KIR and HLA-F in embryo implantation and that the coincidence of unfavorable alleles for both decreases reproductive success considerably, probably due to impaired decidualization and lack of uNK recruitment and activation.
No significant differences were obtained for the rest of the genetic profiles, except when comparing pregnancy rate of KIR AA women with favorable HLA-F alleles to KIR AA women with unfavorable HLA-F alleles for the RS1362126 region (79.41% vs 54.17%, OR = 3.264, p = 0.04). The latter finding suggests that the lack of uNK cell activation, so evident in KIR AA patients, could be compensated by expressing favorable HLA-F alleles.

Limitations, reasons for caution
The low sample size of this study does not allow us to compare groups taking into account other genes, such as embryonic HLA-C, which also, and in combination with KIR genotypes, has been shown to play a role in proper implantation and placentation.

Wider implications of the findings
uNKs activation is required to promote embryo implantation. Combination of unfavorable genetic profiles involved in these immune mechanism leads to lower pregnancy rate. The study of these genetic profiles can help to predict reproductive success, thus identifying patients susceptible to receive immunological treatment before embryo transfer, possibly decreasing their time-to-pregnancy.

Trial registration number
Not applicable