中国组织工程研究

中国组织工程研究 ›› 2023, Vol. 27 ›› Issue (23): 3763-3772.doi: 10.12307/2023.583

• 组织构建循证医学 evidence-based medicine in tissue construction • 上一篇    

亚甲基四氢叶酸还原酶基因多态性与出血性脑卒中相关性的Meta分析

朱俊杰1，王海煌2，李建民1，3，张宇新2，刘俊杰1，3   

  1. 华北理工大学，1临床医学院，2基础医学院，河北省唐山市  063000；3华北理工大学附属医院神经外科，河北省唐山市  063000
  • 收稿日期:2022-08-19 接受日期:2022-09-15 出版日期:2023-08-18 发布日期:2023-01-16
  • 通讯作者: 刘俊杰，讲师，硕士，主治医师，华北理工大学临床医学院，河北省唐山市 063000；华北理工大学附属医院神经外科，河北省唐山市 063000
  • 作者简介:朱俊杰，男，2000年生，安徽省合肥市人，汉族。
  • 基金资助:
    华北理工大学大学生创新创业训练计划项目(X2021142)，项目负责人：朱俊杰；2018年度河北省卫生健康技术研究暨成果转化重点项目(zh2018015)，项目负责人：李建民；河北省临床医学优秀人才培养和基础课题研究项目(361036)，项目负责人：李建民；唐山市科技计划项目(21130224C)，项目负责人：李建民；河北省卫健委医学研究项目(20221533)，项目负责人：李建民

Meta-analysis of the association between methylenetetrahydrofolate reductase gene polymorphisms and hemorrhagic stroke

Zhu Junjie1, Wang Haihuang2, Li Jianmin1, 3, Zhang Yuxin2, Liu Junjie1, 3   

  1. 1School of Clinical Medicine, 2School of Basic Medicine, North China University of Science and Technology, Tangshan 063000, Hebei Province, China; 3Department of Neurosurgery, Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, Hebei Province, China
  • Received:2022-08-19 Accepted:2022-09-15 Online:2023-08-18 Published:2023-01-16
  • Contact: Liu Junjie, Lecturer, Master, Attending physician, School of Clinical Medicine, North China University of Science and Technology, Tangshan 063000, Hebei Province, China; Department of Neurosurgery, Affiliated Hospital of North China University of Science and Technology, Tangshan 063000, Hebei Province, China
  • About author:Zhu Junjie, School of Clinical Medicine, North China University of Science and Technology, Tangshan 063000, Hebei Province, China
  • Supported by:
    Innovation and Entrepreneurship Training Program for College Students of North China University of Science and Technology, No. X2021142 (to ZJJ); 2018 Hebei Health Technology Research and Achievement Transformation Key Project, No. zh2018015 (to LJM); Hebei Province Clinical Medicine Excellent Talents Training and Basic Research Project, No. 361036 (to LJM); Science and Technology Project of Tangshan City, No. 21130224C (to LJM); Medical Research Project of Hebei Provincial Health Commission, No. 20221533 (to LJM)

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摘要：

文题释义：

亚甲基四氢叶酸还原酶基因：该基因编码亚甲基四氢叶酸还原酶，该酶催化 5，10-亚甲基四氢叶酸转化为 5-甲基四氢叶酸，5-甲基四氢叶酸是同型半胱氨酸再甲基化为蛋氨酸的共底物，基因突变可导致该酶缺乏。
出血性脑卒中：一般指非创伤性的颅内血管破裂导致的出血，包括脑出血和蛛网膜下腔出血，具有较高的致残率和死亡率。

目的：亚甲基四氢叶酸还原酶基因C677T或A1298C位点多态性是否与出血性脑卒中相关存在争议。文章以此评估亚甲基四氢叶酸还原酶基因C677T或A1298C位点多态性与出血性脑卒中的相关性。
方法：检索PubMed、Embase、Web of Science、中国知网、万方数据、维普和中国生物医学服务系统(SinoMed)数据库中的相关文献。由2名人员筛选，提取信息和评价文献质量。建立5种遗传模型：等位基因模型(T vs. C 和 C vs. A)、显性模型[(CT+TT) vs. CC 和 (AC+CC) vs. AA]、隐性模型[TT vs. (CC+CT) 和 CC vs. (AA+AC)]、共显性杂合子模型(CT vs. CC 和 AC vs. AA)及共显性纯合子模型(TT vs. CC 和 CC vs. AA)。利用RevMan 5.4和Stata 14软件，Cochrane’ Q检验和I2值评估异质性，合并OR值和95%CI做为效应及指标，亚组分析探索异质性来源，敏感性分析评估结论稳定性，漏斗图、Begg及Egger检验和剪补法评估发表偏倚。
结果：纳入24篇高质量观察性研究文献，其中病例对照研究23篇，横断面研究1篇。①亚甲基四氢叶酸还原酶基因C677T位点多态性与出血性脑卒中存在相关性，5种遗传模型均有显著性意义[T vs. C：OR=1.39，95%CI：1.18-1.64；(CT+TT) vs. CC：OR=1.46，95%CI：1.18-1.80；TT vs. (CC+CT)：OR=1.54，95%CI：1.20-1.96；CT vs. CC：OR=1.31，95%CI：1.08-1.58；TT vs. CC：OR=1.78，95%CI：1.31-2.43]。亚组分析提示在亚洲人群中亚甲基四氢叶酸还原酶基因C677T与出血性脑卒中存在相关性，而欧洲和非洲则无，随着年龄的增大，其OR值越大，在控制病例组和对照组混杂因素(年龄和性别)的研究中，合并效应量提示相关性有显著性意义；综合各项假阳性结果报告率，推测假阳性可能性较小。②亚甲基四氢叶酸还原酶基因A1288C位点多态性与出血性脑卒中相关性无显著性意义[C vs. A：OR=1.16，95%CI：0.98-1.37；(CC+AC) vs. AA：OR=1.19，95%CI：0.96-1.48；CC vs. (AC+AA)：OR=1.27，95%CI：0.86-1.88；AC vs. AA：OR=1.04，95%CI：0.71-1.51；   CC vs. AA：OR=1.37，95%CI：0.90-2.06]；上述位点的亚组分析所得阳性结果，经假阳性结果报告率检验后，结论并不可靠。

结论：亚甲基四氢叶酸还原酶基因C677T位点多态性与出血性脑卒中相关，携带突变T等位基因是出血性脑卒中的重要危险因素，尤其是在亚洲人群中，且年龄越大，风险越大。亚甲基四氢叶酸还原酶基因A1298C位点多态性与出血性脑卒中无明显关联。

https://orcid.org/0000-0002-3339-8700(朱俊杰)；https://orcid.org/0000-0001-5085-802X(刘俊杰)

中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程

关键词: 亚甲基四氢叶酸还原酶基因, MTHFR基因, C677T位点, A1298C位点, 基因多态性, 出血性脑卒中, Meta分析

Abstract: OBJECTIVE: Whether the polymorphisms of methylenetetrahydrofolate reductase C677T or A1298C are associated with hemorrhagic stroke is controversial. Herein, we evaluate the association between the C677T or A1298C polymorphisms of the methylenetetrahydrofolate reductase gene and hemorrhagic stroke.
METHODS: Relevant research literatures were searched in PubMed, Embase, Web of Science, CNKI, WanFang, VIP and SinoMed databases. Two persons screened, extracted information, and assessed the quality of the literature. Five genetic models were established: allelic model (T vs. C and C vs. A), dominant model [(CT+TT) vs. CC and (AC+CC) vs. AA], recessive model [TT vs. (CC+CT) and CC vs. (AA+AC)], codominant heterozygous models (CT vs. CC and AC vs. AA), and codominant homozygous models (TT vs. CC and CC vs. AA). Analyses were performed using RevMan 5.4 and Stata 14 software, Cochrane’ Q test and I2 statistics were used to evaluate heterogeneity, and the combined odds ratio (OR) value and its 95% confidence interval (CI) were used as effect indicators. Subgroup analyses were performed to explore sources of heterogeneity, sensitivity analyses to assess the stability of conclusions, and funnel plots, Begg test, Egger test, and trim and fill methods to assess publication bias. 
RESULTS: Twenty-four high-quality research articles were included, including 23 case-control articles and 1 cross-sectional study. Methylenetetrahydrofolate reductase C677T polymorphism was associated with hemorrhagic stroke, and the five genetic models were statistically significant [T vs. C: OR=1.39, 95% CI: 1.18-1.64; (CT+TT) vs. CC: OR=1.46, 95% CI: 1.18-1.80; TT vs. (CC+CT): OR=1.54, 95% CI: 1.20-1.96; CT vs. CC: OR=1.31, 95% CI: 1.08-1.58; TT vs. CC: OR=1.78, 95% CI: 1.31-2.43]. Subgroup analysis suggested that the methylenetetrahydrofolate reductase C677T was associated with hemorrhagic stroke in Asian populations, but not in Europe and Africa. The OR value increased with aging. In studies controlling for confounding factors (age and sex) in case and control groups, pooled effect sizes suggested a statistically significant correlation. Considering the reporting rates of various false positive results, it is speculated that the possibility of false positives is small. Methylenetetrahydrofolate reductase A1288C polymorphism was insignificantly associated with hemorrhagic stroke [C vs. A: OR=1.16, 95% CI: 0.98-1.37; (CC+AC) vs. AA: OR=1.19, 95% CI: 0.96-1.48; CC vs. (AC+AA): OR=1.27, 95% CI: 0.86-1.88; AC vs. AA: OR=1.04, 95% CI: 0.71-1.51; CC vs. AA: OR =1.37, 95% CI: 0.90-2.06]. The positive results obtained by the subgroup analysis were not reliable after the false positive result reporting rate test. 
CONCLUSION: Overall, methylenetetrahydrofolate reductase C677T locus polymorphism is associated with hemorrhagic stroke, and carrying the mutant T allele is an important risk factor for hemorrhagic stroke, especially in Asian populations, and the older the higher the risk. Methylenetetrahydrofolate reductase A1298C locus polymorphism is insignificantly associated with hemorrhagic stroke.

Key words: methylenetetrahydrofolate reductase gene, MTHFR gene, C677T locus, A1298C locus, gene polymorphism, hemorrhagic stroke, Meta-analysis

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