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中国循证儿科杂志

中国循证儿科杂志 ›› 2024, Vol. 19 ›› Issue (6): 420-427.DOI: 10.3969/j.issn.1673-5501.2024.06.003

• 论著 • 上一篇    下一篇

双亲一碳代谢循环通路关键酶基因序列变异与自然流产的前瞻性遗传关联研究

陈逍天1，张羿1，姚沁玙1，窦亚兰1，何沅宸1，何雯楠1，黄国英2,3，严卫丽1,2   

  1. 1 国家儿童医学中心，复旦大学附属儿科医院，临床流行病学研究室，临床试验工作组上海，201102；2 中国医学科学院小儿遗传相关心血管疾病早期防控创新单元（2018RU002）上海，201102；3 国家儿童医学中心，复旦大学附属儿科医院，心血管中心上海，201102
  • 收稿日期:2024-11-20 修回日期:2024-12-15 出版日期:2024-12-25 发布日期:2024-12-25
  • 通讯作者: 黄国英；严卫丽

One-carbon metabolism key enzymes genetic variants and spontaneous pregnancy loss:A genetic association study

CHEN Xiaotian1, ZHANG Yi1, YAO Qinyu1, DOU Yalan1, HE Yuanchen1, HE Wennan1, HUANG Guoying2,3, YAN Weili1,2   

  1. 1 Department of Clinical Epidemiology & Clinical Trial Unit, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China;2 Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases (2018RU002), Chinese Academy of Medical Sciences, Shanghai 201102, China; 3 Pediatric Heart Center, Children's Hospital of Fudan University, National Children's Medical Center, Shanghai 201102, China
  • Received:2024-11-20 Revised:2024-12-15 Online:2024-12-25 Published:2024-12-25
  • Contact: HUANG Guoying;YAN Weili

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摘要： 背景一碳代谢循环（OCM）是维持胚胎正常发育的关键信号通路之一，双亲OCM循环通路关键酶基因序列变异与自然流产(SPL)的关系缺乏高质量研究证据。 目的探讨男女双方OCM循环通路关键酶基因序列变异与SPL的关联。 设计前瞻性队列研究。 方法以上海孕前亲子队列中自2018年9月至2023年10月招募的参加孕前或婚检的夫妻双方、完成基因分型、并在2023年10月前完成分娩的家庭为研究对象。根据既往的研究基础，选择与红细胞叶酸水平变化贡献最大的、且有明确重要生物学功能的5个单核苷酸多态位点纳入分析（MTHFR基因rs1801133、MTRR基因rs1801394和rs326119、MTHFD1基因rs2236225、FIGN 基因rs2119289）。采用实时荧光定量 PCR 技术进行基因分型。将妊娠期间发生的所有妊娠失败或胚胎死亡事件定义为SPL。通过广义线性模型分析男女双方5个单核苷酸多态位点与SPL的关联，调整年龄、孕前BMI、孕次、不良妊娠史、烟草暴露、饮酒和红细胞叶酸，报告调整的风险比（aRR）以及95%CI。根据不同国家和地区关于SPL定义的差异，分别针对主要结果进行敏感性分析以评估主要结果的稳定性。 主要结局指标孕前双亲OCM循环通路关键酶基因SNPs与SPL的关联。 结果在纳入的4 145对备孕夫妻中，随访到SPL 230例（5.5%）。男方MTHFR基因rs1801133 C>T变异与25%的SPL风险升高显著相关，调整协变量后，aRR（95% CI）为1.25（1.03~1.52），P=0.024。与男方rs1801133 CC基因型携带者相比，TT基因型携带者发生SPL的风险升高58%［aRR（95%CI）=1.58（1.08~2.32）；P=0.018］；未发现女方MTHFR基因rs1801133与SPL有显著关联。与女方FIGN基因rs2119289 GG基因型携带者相比，CC基因型携带者发生SPL的风险下降28%［aRR（95% CI）=0.72（0.53~0.98）；P=0.036］；未发现男方FIGN基因rs2119289位点与SPL有显著关联。敏感性分析结果与主要结果一致。 结论男方MTHFR基因rs1801133位点和女方FIGN基因rs2119289位点序列变异与SPL显著关联，可能是SPL的遗传易感位点。

关键词: 自然流产, 前瞻性队列, 一碳代谢, 遗传关联

Abstract: BackgroundThe one-carbon metabolism (OCM) cycle is a critical signaling pathway for normal embryonic development. However, high-quality evidence on the association between parental OCM pathway enzyme gene variants and spontaneous pregnancy loss (SPL) remains limited. ObjectiveTo investigate the association between key enzyme gene variants in the OCM pathway in both parents and the occurrence of SPL. Design Prospective cohort study. MethodsThis study included couples recruited from the Shanghai Preconception Cohort between September 2018 and October 2023. Participants were couples who underwent preconception or premarital medical examinations, completed genetic genotyping, and had pregnancy outcomes recorded by October 2023. Based on previous research, five single nucleotide polymorphisms (SNPs) known for their significant contributions to variations in red blood cell folate levels and important biological functions were selected for analysis: MTHFR rs1801133, MTRR rs1801394 and rs326119, MTHFD1 rs2236225, and FIGN rs2119289. Genotyping was performed using real-time fluorescence quantitative PCR. SPL was defined as any pregnancy loss or embryonic demise occurring during gestation. Generalized linear models were used to analyze the association between parental SNPs and SPL, adjusting for covariates including age, pre-pregnancy BMI, gravidity, history of adverse pregnancy outcomes, tobacco exposure, alcohol consumption, and red blood cell folate levels. Adjusted risk ratios (aRR) and 95% confidence intervals (CI) were reported. Sensitivity analyses were conducted based on different SPL definitions used across various countries and regions to assess the robustness of the main findings. Main outcome measuresThe association between parental SNPs in the OCM pathway and SPL. ResultsA total of 4,145 couples were included in the analysis, among whom 230 cases of SPL (5.5%) were recorded. The paternal MTHFR rs1801133 C>T variant was significantly associated with a 25% increased risk of SPL. After adjusting for covariates, the aRR (95%CI) was 1.25 (1.03-1.52), P=0.024. Compared with fathers carrying the MTHFR rs1801133 CC genotype, those with the TT genotype had a 58% higher risk of SPL ［aRR (95%CI)=1.58 (1.08-2.32), P=0.018］. No significant association was found between maternal MTHFR rs1801133 and SPL. Meanwhile, maternal FIGN rs2119289 CC genotype carriers had a 28% lower risk of SPL compared to those with the GG genotype ［aRR (95%CI)=0.72 (0.53-0.98), P=0.036］. No significant association was observed between paternal FIGN rs2119289 and SPL. Sensitivity analyses yielded results consistent with the primary findings. ConclusionThe MTHFR rs1801133 variant in fathers and the FIGN rs2119289 variant in mothers were significantly associated with SPL, suggesting that these loci may be genetic susceptibility markers for pregnancy loss.

Key words: Spontaneous pregnancy loss, Prospective cohort, One-carbon metabolism, Genetic association