DataSheet_1_Association of parental HLA-G polymorphisms with soluble HLA-G expressions and their roles on recurrent implantation failure: A systematic review and meta-analysis.docx

IntroductionHLA-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.
MethodsStudies 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.
ResultsHLA-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.
DiscussionSpecific 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.

引言
人类白细胞抗原G（HLA-G）在母胎界面的免疫耐受中发挥核心作用。与经典HLA基因相比，HLA-G基因具有等位基因多态性低、组织表达受限的特征。HLA-G的多态性与HLA-G的表达相关，且与妊娠并发症存在关联。然而，亲本HLA-G多态性与可溶性HLA-G（soluble HLA-G，sHLA-G）表达之间的关联，及其在反复植入失败（recurrent implantation failure，RIF）中的作用目前尚不明确。本研究旨在系统评价接受体外受精（in-vitro fertilization，IVF）治疗的患者中，HLA-G多态性与RIF的关联、sHLA-G表达与RIF的关联，以及HLA-G多态性与sHLA-G表达之间的关联。

方法
纳入评估接受IVF治疗的患者中，HLA-G多态性与RIF的关联、sHLA-G表达与RIF的关联，以及HLA-G多态性与sHLA-G表达之间关联的相关研究。采用随机效应模型开展荟萃分析（Meta-analysis）。通过每次剔除一项研究的方式进行敏感性分析。基于种族进行亚组分析。

结果
HLA-G的14bp插入变异与接受IVF治疗的夫妇精液或血浆中的sHLA-G低表达相关。与其他等位基因相比，母体HLA-G*010101等位基因及父体HLA-G*010102等位基因与RIF风险相关。然而，在普通人群中，单一母体HLA-G 14bp插入/缺失多态性、HLA-G -725 C>G/T多态性或循环sHLA-G浓度与RIF无显著关联。在高加索人群中，HLA-G 14bp插入/插入纯合基因型或插入变异与RIF的更高风险相关。

讨论
特定的HLA-G等位基因或HLA-G多态性与接受IVF治疗的夫妇的sHLA-G表达相关。考虑到不同的种族背景，多种HLA-G多态性可能与RIF相关。未来的研究应考虑联合遗传效应，以明确HLA-G多态性与sHLA-G表达之间的关联及其与RIF的关系。