O-034 Specific KIR gene profiles and recurrent implantation failure
Authors: Andreeva P , Oprova I , Hristova-Savova M , Belemezova K , Shterev A , Dimova I 
Published: July 2024

Abstract

Study question
Is there a link between killer cell immunoglobulin-like receptors (KIRs) genes, haplotypes, or genotypes and recurrent implantation failure (RIF)?

Summary answer
The KIRAA1 genotype significantly increases the risk of RIF. The presence of the full-length receptor KIR2DS4norm in KIRAA haplotype patients is indicative of RIF development.

What is known already
KIRs are expressed by a subset of uterine natural killer cells (uNK cells). The KIRs family consists of 16 genes with high polymorphism that are divided into two main haplotypes: KIRAA and KIRBx. The KIRAA haplotype consists mostly of inhibitory KIRs and only one activating receptor, KIR2DS4, whose function is uncertain, whereas the Bx haplotype has a diverse gene composition, with a focus on activating receptor genes. The primary difference is in the balance of KIRs, which can activate or inhibit uNKcells’ ability to produce components required for embryo-implantation, and hence they are thought to being implicated in RIF.

Study design, size, duration
A three-year observational cohort research was conducted at a private infertility centre. A total of 82 patients were genotyped for activating or inhibiting KIR genes. The study included 60 ovarian normo-responders under the age of 40, with 28 women with repeated implantation failure serving as the study group and 32 as controls.

Participants/materials, setting, methods
DNA was extracted from blood samples of all participants, including RIF patients and controls. The 16 KIR genes were investigated utilizing PCR with Sequence-Specific Primer (SSP) technique. Individual KIR gene profiles, KIRAA and KIRBx haplotypes, and their unique genotypes were detected by software analyses of the collected data based on the reaction pattern when compared to patterns associated with described KIR gene sequences. All data were statistically analysed with the Fisher Exact Test.

Main results and the role of chance
The frequencies of the two main haplotypes, KIR AA and KIR Bx, were 28% and 72%, respectively. Patients with more inhibitory KIR genes (haplotype KIR AA) had a higher rate of RIF (60% vs 40% in controls; P = 0.2) than those with KIR Bx phenotypes (37.5% RIF vs 62.5% controls; p = 0.026). Further analysis of KIR AA revealed two genotypes: KIR AA 1 (31.82%) and KIR AA195 (68.18%). The KIR2DS4 locus in the full-length receptor (KIR2DS4-norm) was only expressed in KIR AA1. The distribution of RIF occurrences in the two different genotypes demonstrates a significant increase in the number of RIF in the possessors of KIR AA1 (75% vs 15%, p = 0.01), with no significant difference between the two groups in the KIR AA195.

Limitations, reasons for caution
The study encompasses small samples but the association strength was noticeably high, which confers the findings more confidence.

Wider implications of the findings
These findings imply that women with a high proportion of inhibited KIR genes (haplotype KIR AA) and KIR2DS4norm are more likely to develop RIF.

Trial registration number
NA