Supplementary Material for: Meta-Analysis of Human Leukocyte Antigen-G 3′UTR Polymorphisms Confer Susceptibility to Recurrent Miscarriage

Objectives: The current systematic review and meta-analysis have shown that specific HLA-G 3′ UTR variants are associated with recurrent miscarriage (RM). Our aim was to investigate the relevance of HLA-G 3′ UTR polymorphisms with the risk of RM. Design: A combined meta-analysis was implemented in this study. Participants/Materials, Setting, Methods: Common electronic databases including PubMed, Embase, Web of Science, China National Knowledge Infrastructure, Cochrane Library, and Google Scholar were used to seek eligible articles up to August 2021. Results: Forty-four eligible articles with 4,467 cases and 3,955 controls were finally enrolled. Our meta-results suggested that 14 bp insertion allele was associated with elevated risk of RM (allelic model: OR = 1.18, 95% CI = 1.07–1.31, p = 0.001). Besides, a significant heterogeneity was observed between studies. Further subgroup analyses based on ethnicity revealed similar positive results in both the Caucasian and Asian subgroups but not in the Middle East subgroup. Moreover, rs1063320 G allele conferred elevated susceptibility to RM in Asian group (allelic model: OR = 1.54, 95% CI = 1.17–2.03, p = 0.002). Additionally, pooled results showed a decreased risk of RM in mothers carrying rs1710 G allele (allelic model: OR = 0.68, 95% CI = 0.55–0.85, p p = 0.002). Further stratified analyses by race showed that these positive results were mainly from the associations observed in Asian populations. Limitations: The main limitation is that the enrolled number of individuals was relatively small. Thus, the results should be cautiously considered. Conclusions: Although the current systematic review and meta-analysis have shown that specific HLA-G 3′ UTR variants are associated with RM, a high degree of bias is present and further studies are needed to validate this causative effect.研究目的：现有系统评价与荟萃分析已证实，特定人类白细胞抗原G（HLA-G）3'非翻译区（3' UTR）变异与复发性流产（recurrent miscarriage, RM）存在关联。本研究旨在探讨HLA-G 3'UTR基因多态性与复发性流产发病风险的相关性。 研究设计：本研究采用联合荟萃分析方法。 研究对象/材料、研究场景与方法：检索截至2021年8月的PubMed、Embase、Web of Science、中国知网（China National Knowledge Infrastructure, CNKI）、Cochrane图书馆及Google Scholar等常用电子数据库，以筛选符合纳入标准的研究文献。 研究结果：最终纳入44篇符合标准的文献，涵盖4467例病例组与3955例对照组。本研究的荟萃分析结果显示，14 bp插入等位基因与复发性流产发病风险升高存在显著关联（等位基因模型：优势比（odds ratio, OR）=1.18，95%置信区间（confidence interval, CI）=1.07~1.31，p=0.001）。此外，各研究间存在显著异质性。基于种族的亚组分析进一步显示，高加索人群与亚洲人群亚组均得到相似的阳性结果，但中东人群亚组未观察到该关联。此外，rs1063320位点G等位基因可增加亚洲人群发生复发性流产的易感性（等位基因模型：OR=1.54，95%CI=1.17~2.03，p=0.002）。此外，合并分析结果显示，携带rs1710位点G等位基因的母亲发生复发性流产的风险降低（等位基因模型：OR=0.68，95%CI=0.55~0.85，p=0.002）。按种族进行的分层分析进一步表明，上述阳性关联主要来源于亚洲人群的研究数据。 局限性：本研究的主要局限性为纳入的研究对象数量相对较少，因此对本研究结果的解读应保持谨慎。 研究结论：尽管当前的系统评价与荟萃分析已证实特定HLA-G 3'UTR变异与复发性流产存在关联，但本研究仍存在较高偏倚，需开展进一步研究以验证该因果关联。