Association of parental HLA-G polymorphisms with soluble HLA-G expressions and their roles on recurrent implantation failure: A systematic review and meta-analysis

Abstract

Introduction: HLA-G plays a central role in immune tolerance at the maternal-fetal interface. The HLA-G gene is characterized by low allelic polymorphism and restricted tissue expression compared with classical HLA genes. HLA-G polymorphism is associated with HLA-G expression and linked to pregnancy complications. However, the association of parental HLA-G polymorphisms with soluble HLA-G (sHLA-G) expression and their roles in recurrent implantation failure (RIF) is unclear. The study aims to systematically review the association of HLA-G polymorphisms with RIF, the association of sHLA-G expression with RIF, and the association of HLA-G polymorphisms with sHLA-G expressions in patients attending in-vitro fertilization (IVF) treatment.

Methods: Studies that evaluated the association of HLA-G polymorphisms with RIF, the association between sHLA-G expression with RIF, and the association between HLA-G polymorphisms with sHLA-G expressions in patients attending IVF treatment were included. Meta-analysis was performed by random-effect models. Sensitivity analysis was performed by excluding one study each time. Subgroup analysis was performed based on ethnicity.

Results: HLA-G 14bp ins variant is associated with a lower expression of sHLA-G in seminal or blood plasma of couples attending IVF treatment. The maternal HLA-G*010101 and paternal HLA-G*010102 alleles are associated with RIF risk compared to other alleles. However, single maternal HLA-G 14bp ins/del polymorphism, HLA-G -725 C>G/T polymorphism, or circulating sHLA-G concentration was not significantly associated with RIF in the general population. HLA-G 14bp ins/ins homozygous genotype or ins variant was associated with a higher risk of RIF in the Caucasian population.

Discussion: Specific HLA-G alleles or HLA-G polymorphisms are associated with sHLA-G expression in couples attending IVF treatment. Several HLA-G polymorphisms may be related to RIF, considering different ethnic backgrounds. A combined genetic effect should be considered in future studies to confirm the association of HLA-G polymorphisms and sHLA-G expressions in relation to RIF.

Keywords: Human leukocyte antigen G; genetic polymorphism; immune tolerance; meta-analysis; recurrent implantation failure.

Figure 1

Flow chart of study selection.

Figure 2

Forest plot showing the association of HLA-G 14bp ins/del polymorphism with RIF under 5 genetic models.

Figure 3

Forest plot showing subgroup analyses based on ethnicity and sensitivity analysis by omitting one study each time.

Figure 4

Forest plot showing the association of HLA-G -725C>G/T polymorphism with RIF under 5 genetic models.

Figure 5

Forest plot showing the association of parental HLA-G allele distribution with RIF.

Figure 6

Forest plot showing the association of circulating sHLA-G concentration with RIF.

Figure 7

Forest plot showing the association of parental HLA-G 14bp ins/del polymorphism with sHLA-G expression in seminal plasma or in blood plasma. (A) Meta-analysis of sHLA-G expression in male seminal plasma in comparison of ins/ins genotype versus del/del genotype. (B) Meta-analysis of sHLA-G expression in male seminal plasma in comparison of ins/ins genotype versus ins/del genotype. (C) Meta-analysis of sHLA-G expression in male seminal plasma in comparison of ins/del genotype versus del/del genotype. (D) Meta-analysis of sHLA-G expression in male seminal plasma in comparison of ins/ins genotype versus ins/del+del/del genotype. (E) Meta-analysis of sHLA-G expression in male seminal plasma in comparison of ins/ins+ins/del genotype versus de/del genotype. (F) Meta-analysis of sHLA-G expression in female blood plasma in comparison of ins/ins genotype versus ins/del+del/del genotype.