Polimorfismos do antígeno leucocitário humano (HLA) e sua ligação com a infertilidade

Abstract

Infertility affects approximately one in six people of reproductive age globally, and about 15% of cases remain without an identified cause after standard investigation, being classified as unexplained infertility. Emerging evidence points to the immune system as a critical factor in these cases, particularly concerning maternal-fetal tolerance mediated by the Human Leukocyte Antigen (HLA) system. The present study consists of an integrative literature review aimed at investigating the association between HLA gene polymorphisms and adverse reproductive outcomes. The search was conducted in the PubMed and Academic Search Premier databases, covering publications between 2020 and 2025, resulting in the selection of 21 original studies and meta-analyses. The findings were organized into summary tables and critically analyzed. Regarding HLA-G, evidence demonstrated that the 14-bp INS/DEL polymorphism is associated with recurrent pregnancy loss (RPL), with effects dependent on haplotypic context and ethnicity. HLA-F emerged as a novel player in implantation, with endometrial expression modulated by SNPs rs1362126, rs2523405, and rs2523393, and correlated with regulatory T cells. HLA-E showed a significant association with male infertility (HLA-E*01:01 genotype) but not with female outcomes. The HLA-C/KIR/ERAP axis revealed complex interactions: the KIR Tel AA + HLA-C2C2 combination conferred risk for recurrent implantation failure (RIF), a risk modulated by polymorphisms in ERAP1 (rs26653, rs26618, rs27044, rs30187), with serum ERAP2 levels emerging as a potential prognostic biomarker. HLA class II genes (DRB1, DQB1, DQA1, DPB1) showed markedly population-specific associations, notably the sharing of one HLA-DQB1 allele between spouses in 46% of couples with RPL in the Chinese population. The marked population heterogeneity observed reinforces the need for studies in diverse ethnic groups and caution in generalizing findings. It is concluded that polymorphisms of the HLA system and correlated genes constitute central elements in the etiology of immune-mediated infertility, acting in complex interaction networks involving haplotypes, epistasis, and parental genotypic combinations.