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  

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

作　　者：陈逍天 张羿 姚沁玙 窦亚兰 何沅宸 何雯楠 黄国英 严卫丽 CHEN Xiaotian;ZHANG Yi;YAO Qinyu;DOU Yalan;HE Yuanchen;HE Wennan;HUANG Guoying;YAN Weili(Department of Clinical Epidemiology&Clinical Trial Unit,Children's Hospital of Fudan University,National Children's Medical Center,Shanghai 201102,China;Research Unit of Early Intervention of Genetically Related Childhood Cardiovascular Diseases(2018RU002),Chinese Academy of Medical Sciences,Shanghai 201102,China;Pediatric Heart Center,Children's Hospital of Fudan University,National Children's Medical Center,Shanghai 201102,China)

机构地区：[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

出　　处：《中国循证儿科杂志》2024年第6期420-427,共8页Chinese Journal of Evidence Based Pediatrics

基　　金：上海市卫生健康委员会启明星培育“扬帆专项”:20214Y0439;国家重点研发计划:2021YFC2701004;中国医学科学院医学与健康科技创新工程项目:2019-I2M-5-002;国家自然科学基金青年项目:82204051,2024YFC2707600;国家自然科学基金面上项目:82373584、82070323。

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4145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�Background The 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.Objective To investigate the association between key enzyme gene variants in the OCM pathway in both parents and the occurrence of SPL.Design Prospective cohort study.Methods This 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 measures The association between parental SNPs in the OCM pathway and SPL.Results A 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.

关 键 词：自然流产 前瞻性队列 一碳代谢 遗传关联 

分 类 号：R73[医药卫生—肿瘤]