HLA-C (C1/C2) Genotyping

HLA-C typing at the allelic resolution level is used for the detailed determination of HLA-C gene variants. This gene plays a crucial role in the communication between the mother's immune system and the developing embryo during pregnancy. HLA-C analysis helps identify specific combinations of maternal and fetal genes that may be associated with a higher risk of complications such as recurrent miscarriages, preeclampsia, intrauterine growth restriction (IUGR), or preterm birth. We recommend combining it with the KIR haplotype determination method.

Successful pregnancy requires the establishment of immunotolerance at the maternal-fetal interface. This process is mediated by the interaction between specialized maternal immune cells present in the uterus, known as uterine Natural Killer (uNK) cells, and the developing embryo. uNK cells recognize the embryo through receptors on their surface called Killer-cell Immunoglobulin-like Receptors (KIRs). These receptors bind to specific identification molecules on the embryo's surface, which are the HLA-C molecules.

Numerous scientific studies have demonstrated that certain combinations of maternal KIR receptors and fetal HLA-C molecules can increase the likelihood of complications during pregnancy. The genes encoding KIR receptors are located on chromosome 19q13.4 within the leukocyte receptor complex region. To date, 17 different KIR genes have been identified – nine genes for inhibitory receptors, six for activating receptors, and two pseudogenes. Based on genetic variability, these genes are divided into two main haplotypes: haplotype A (KIR A) and haplotype B (KIR B). KIR haplotypes represent specific combinations of centromeric and telomeric regions with frequent recombinations between them. During each pregnancy, a mother can have one of three KIR genotypes: AA (predominantly inhibitory KIRs), AB (a combination of inhibitory and activating KIRs), or BB (a higher number of activating KIRs).

HLA-C gene, which belong to the HLA class I gene group, is located on the short arm of chromosome 6. HLA-C plays a unique role in pregnancy as it is the only classical HLA class I gene expressed at the maternal-fetal interface. HLA-C ligands for KIR receptors are divided into two functional groups: HLA-C1 and HLA-C2. Ligands of the C2 group exhibit a stronger binding affinity to certain KIR receptors than ligands of the C1 group.

Haplotype A is characterized by a predominance of genes for inhibitory KIR receptors, while haplotype B contains more genes encoding activating KIR receptors. Research suggests that in women with the KIR AA genotype (homozygous for haplotype A) carrying a fetus expressing the HLA-C2 epitope, there is a higher likelihood that the trophoblast (the tissue forming the placenta) will be unable to ensure sufficient perfusion of the placenta with maternal blood. This condition can lead to embryo implantation failure, recurrent pregnancy loss, an increased risk of preeclampsia, intrauterine growth restriction (IUGR), or preterm birth.

The risk of complications appears to be even higher if the fetus inherits more HLA-C2 alleles than the mother, and especially if these fetal HLA-C2 alleles are of paternal origin. In the context of donated oocyte cycles, which are increasingly common in women of advanced reproductive age, the HLA-C of the oocyte, being genetically different from the mother's HLA-C, behaves similarly to paternal HLA-C. This means that even in these cases, immune incompatibility between the mother and the developing fetus can occur, potentially affecting the course of pregnancy.

HLA-C typing at the allelic (high) resolution level is a sophisticated genetic analysis that determines the variants (alleles) of the HLA-C gene with high accuracy. This analysis is performed using the polymerase chain reaction with sequence-specific primers (PCR-SSP) method using an IVD kit. If a patient has undergone testing with us using the NGS method since 2024, we will perform the analysis from the NGS data. The identified alleles of the HLA-C gene are classified into two main groups, C1 and C2, based on their genetic characteristics.