JBRA Assisted Reproduction 2025;29(Suppl.2 SBRA 2025):187
Poster Presentation
29^th Annual Congress of the SBRA. São Paulo/SP - Brazil, 2025
doi: 10.5935/1518-0557.20263899

P-175. Polymorphisms of Human Leukocyte Antigen (Hla) and Their Relationship with Infertility: Current Evidence

Maria Bárbara Moreira Souza¹, Priscilla Anne Castro Assis¹

¹ Universidade Federal da Paraíba - João Pessoa – PB - Brasil

Objective: To investigate the association between Human Leukocyte Antigen (HLA) polymorphisms and reproductive failures, focusing on the immunological mechanisms involved in embryonic rejection and pregnancy loss. The following aspects were considered: identification and characterization of HLA polymorphisms associated with maternal-fetal immune tolerance failure; correlation of HLA molecule expression patterns with adverse outcomes; evaluation of the diagnostic potential of HLA markers; comparison of allele frequency in women with a history of recurrent losses and controls; and critical analysis of the evidence regarding the role of HLA in gestational immunomodulation.
Methods: An integrative review was conducted in the PubMed database using descriptors related to HLA, genetic variations, and reproductive failures. Original studies and meta-analyses in humans, published in English between 2020 and the present, that evaluated HLA polymorphisms and reproductive failures including embryonic rejection, recurrent implantation failure (RIF), recurrent pregnancy loss (RPL), and recurrent miscarriage (RM). Review articles without primary data, animal studies, in vitro models, and duplicates were excluded. After screening, 13 articles comprised the final sample. Extracted data included: authors, year/location, sample characteristics, genotyping methods, evaluated polymorphisms, statistical results, and conclusions.
Results: A consistent association was observed between polymorphisms in the major histocompatibility complex and infertility, particularly in RPL and RIF. Among class I genes, the following stood out: HLA-C12:02 and HLA-B52:01 as risk factors for RPL in Japanese women; interactions between maternal/paternal HLA-C and ERAP1 gene variants modulating RIF risk; and HLA-G, whose haplotypes PROMO-G010104-UTR-3 and the 14-bp insertion were associated with lower sHLA-G expression and worse outcomes, while the UTR-4 haplotype was protective. Among class II genes, HLA-DRB1 07 was associated with RPL, and HLA-DQ2/DQ8 was more prevalent in women with RPL, linked to autoimmune markers. Other risk alleles included DQB102:01:01 (RIF and RPL) and C12:02:01 (RPL). Protective alleles included C07:02:01, DQB102:02:01, and DQB106:03. Meta-analyses confirmed the association of the HLA-G 14-bp ins/del with RPL but not with RIF and identified variants such as rs1063320 and rs9380142 as influential, particularly in Asian populations. Ethnic and methodological differences partly explained the observed heterogeneity. HLA polymorphisms influence maternal-fetal immune recognition, uterine NK cell regulation, and local inflammatory responses. Risk alleles such as HLA-C12:02, HLA-DRB1 07, and HLA-DQB1 02:01:01 may induce an incompatible immune response against the embryo, whereas protective alleles like HLA-DQB1 06:03 promote a tolerogenic environment. HLA-G is a relevant marker of maternal-fetal tolerance, with the 14-bp insertion associated with lower sHLA-G expression and worse prognosis, varying by ethnicity. The interaction between ERAP1 variants and HLA-C highlights that genetic compatibility between partners may be determinant in reproductive success. The modulation of HLA-F and HLA-G by hormonal environment reinforces the multifactorial nature of immune tolerance balance in pregnancy. Despite consistent findings, limitations such as definition heterogeneity, ethnic variability, and methodological differences complicate cross-study comparisons, and few studies explore the interaction of multiple HLA loci with environmental factors.
Conclusion: HLA polymorphisms are strongly associated with infertility, particularly in RPL and RIF. Alleles such as HLA-C12:02, HLA-DRB1 07, HLA-DQB1 02:01:01, and the HLA-G 14-bp insertion are risk markers, whereas HLA-DQB1 06:03 has a protective effect. Associations vary by population, reinforcing the need for personalized approaches in reproductive counseling.