Maternal HLA‐C2 and 14 bp insertion in HLA‐G is associated with recurrent implantation failure after in vitro fertilization treatment

Abstract

The major rate-limiting step in in vitro fertilization (IVF) success appears to be the implantation of the semi-allogeneic embryo into the maternal endometrium. To determine possible risk factors of recurrent failure of embryos to implant, we investigated immunogenetic determinants as level of human leukocyte antigen (HLA) histocompatibility, frequency of killer-cell immunoglobulin-like receptors (KIR) and HLA-C alleles and HLA-G polymorphism. We DNA typed women with recurrent implantation failure (RIF) and their partners for classical HLA Class I, HLA Class II, HLA-G and KIR alleles and compared these results with couples with successful embryo implantation after their first IVF and normal fertile couples. No association was found between RIF and the degree of histocompatibility between partners or sharing of a specific antigen. Also, no significant difference in KIR haplotype or combination of HLA-C group and KIR was observed. We did find a higher frequency of HLA-C2 and a higher frequency of 14 base pair (bp) insertion in HLA-G in women with RIF. Therefore we conclude that the degree of histocompatibility between partners is not a determining factor for the occurrence of RIF. However, presence of the HLA-C2 allotype and the HLA-G allele with a 14 bp insertion is a significant risk factor.

Genetic association between HLA-G 14-bp polymorphism and diseases: A systematic review and meta-analysis

“…Notwithstanding that, this meta-analysis revealed inconsistencies between some association studies that have already been published. This statement is based on the following results: i) when we observed data from many conditions (Cervical cancer, Hepatocellular carcinoma, Multiple sclerosis, Rheumatoid arthritis, HIV vertical transmission, Human papillomavirus infection, Heart transplantation, Kidney transplantation, Preeclampsia (mothers), Implantation failure, Miscarriage, e.g), we could verify that some studies found the 14-bp insertion associated with susceptibility to disease development [108,112,[117][118][119]138,140], whereas, others revealed the 14-bp deletion as the allele associated with susceptibility [47,53,79,82,91], and sometimes none was associated [48,49,80,98,101,105,147]; ii) when the disorders were grouped according to conditions exhibiting a hypothetical high (1) or low (2) HLA-G expression, no associations between the 14-bp alleles were All possible associations between 14-bp polymorphism and the clinical situations/diseases were measured by calculating a pooled Odds Ratio (OR) and 95% confidence intervals (CI) for fixed and/or random effect models. The p values resulting from the Q test, τ2 values and of the I2 value were used to measure betweenstudies heterogeneity.…”

Association of Soluble HLA-G Plasma Level and HLA-G Genetic Polymorphism With Pregnancy Outcome of Patients Undergoing in vitro Fertilization Embryo Transfer

“…Only GG genotype in promoter rs1632947: c.-964G>A was linked with protection against infertility, while the most studied HLA-G polymorphism in the field of reproduction, rs371194629: c. * 65_ * 66insATTTGTTCATGCCT in 3 ′ UTR of exon 8, had a similar distribution in our group of patients and controls ( Table 2). Other epidemiological studies concerning the role of 14-bp ins/del polymorphism in RIF provided apparently inconclusive results, which might be due to differences in the studied populations and limited sample sizes (50)(51)(52). However, a recently published meta-analysis (37) on the impact of 14-bp ins/del polymorphism in recurrent miscarriage after natural or artificial conception revealed that women of European countries with the HLA-G 14-bp insertion/insertion homozygous genotype have a significantly higher prevalence of recurrent miscarriage.…”

Next‐generation sequencing of HLA‐G based on long‐range polymerase chain reaction

“…The HLA‐G molecule has a unique expression pattern and was first described on fetal extra‐villous trophoblast cells at the feto‐maternal interface during pregnancy . HLA‐G has immunosuppressive characteristics, protecting the developing fetus from the mother's immune system, and aberrant HLA‐G expression may well be a part of the pathogenesis of certain pregnancy complications and reduced fertility …”

“…6,7 HLA-G has immunosuppressive characteristics, protecting the developing fetus from the mother's immune system, and aberrant HLA-G expression may well be a part of the pathogenesis of certain pregnancy complications and reduced fertility. 4,8,9 Classical HLA genes are usually haplotyped by the sequence of a few exons defining the peptide presenting regions of the molecule. For HLA-G, it has become increasingly evident that variants positioned in noncoding regions are of importance because of the influence on the expression level and splicing of different HLA-G isoforms.…”