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Background <p>Recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder in which epigenetic dysregulation has been increasingly implicated. DNA methylation of immune-regulatory genes, particularly human leukocyte antigen-G (HLA-G), may impair maternal–fetal immune tolerance and contribute to adverse pregnancy outcomes. This study investigated the association between HLA-G promoter methylation and circulating HLA-G levels in women with unexplained RPL.</p> Methods and results <p>A case–control study was conducted including 100 women with unexplained RPL and 100 age- and matched healthy parous controls. Bisulfite-treated DNA was analyzed for HLA-G promoter methylation using methylation-specific PCR, while plasma HLA-G concentrations were quantified by ELISA. Statistical analyses included group comparisons, correlation analysis, and receiver operating characteristic (ROC) curve analysis. Women with RPL exhibited significantly lower plasma HLA-G levels compared with controls (97.3 ± 19.0 vs. 106.1 ± 10.3; <i>p</i> &lt; 0.05). The frequency of methylated HLA-G promoter alleles was significantly higher in the RPL group (62%) than in controls (24%) (<i>p</i> &lt; 0.05). A modest but significant inverse association was observed between HLA-G promoter methylation and plasma HLA-G levels (<i>p</i> = 0.010). ROC analysis demonstrated high specificity (97%) but limited sensitivity (48%), with a low area under the curve (AUC = 0.348).</p> Conclusion <p>Increased HLA-G promoter methylation and reduced circulating HLA-G levels are associated with recurrent pregnancy loss, supporting a contributory role of epigenetic regulation in RPL. However, HLA-G promoter methylation alone shows limited predictive utility and may be more informative when integrated with additional molecular or clinical markers.</p>

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Epigenetic regulation of HLA-G : implications for recurrent pregnancy loss

  • 期刊论文

  • 发表日期：

    2026年3月28日

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  • Mai M. Shaker,
  • Nesma M. Elaraby,
  • Taghreed A. Shalabi

摘要

Background

Recurrent pregnancy loss (RPL) is a multifactorial reproductive disorder in which epigenetic dysregulation has been increasingly implicated. DNA methylation of immune-regulatory genes, particularly human leukocyte antigen-G (HLA-G), may impair maternal–fetal immune tolerance and contribute to adverse pregnancy outcomes. This study investigated the association between HLA-G promoter methylation and circulating HLA-G levels in women with unexplained RPL.

Methods and results

A case–control study was conducted including 100 women with unexplained RPL and 100 age- and matched healthy parous controls. Bisulfite-treated DNA was analyzed for HLA-G promoter methylation using methylation-specific PCR, while plasma HLA-G concentrations were quantified by ELISA. Statistical analyses included group comparisons, correlation analysis, and receiver operating characteristic (ROC) curve analysis. Women with RPL exhibited significantly lower plasma HLA-G levels compared with controls (97.3 ± 19.0 vs. 106.1 ± 10.3; p < 0.05). The frequency of methylated HLA-G promoter alleles was significantly higher in the RPL group (62%) than in controls (24%) (p < 0.05). A modest but significant inverse association was observed between HLA-G promoter methylation and plasma HLA-G levels (p = 0.010). ROC analysis demonstrated high specificity (97%) but limited sensitivity (48%), with a low area under the curve (AUC = 0.348).

Conclusion

Increased HLA-G promoter methylation and reduced circulating HLA-G levels are associated with recurrent pregnancy loss, supporting a contributory role of epigenetic regulation in RPL. However, HLA-G promoter methylation alone shows limited predictive utility and may be more informative when integrated with additional molecular or clinical markers.