Chinese Journal of Tissue Engineering Research ›› 2023, Vol. 27 ›› Issue (23): 3763-3772.doi: 10.12307/2023.583
Zhu Junjie1, Wang Haihuang2, Li Jianmin1, 3, Zhang Yuxin2, Liu Junjie1, 3
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:
CLC Number:
Zhu Junjie, Wang Haihuang, Li Jianmin, Zhang Yuxin, Liu Junjie. Meta-analysis of the association between methylenetetrahydrofolate reductase gene polymorphisms and hemorrhagic stroke[J]. Chinese Journal of Tissue Engineering Research, 2023, 27(23): 3763-3772.
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2.2 Meta分析结果 2.2.1 MTHFR基因C677T位点多态性与出血性脑卒中相关性 建立下述遗传模型分别进行分析,等位基因模型T vs. C,显性模型(CT+TT) vs. CC,隐性模型TT vs.(CC+CT),共显性杂合子模型CT vs. CC,共显性纯合子模型TT vs. CC。如表4所示,5种遗传模型均存在明显的研究异质性(I2≥50%,P < 0.05),因此采用随机效应模型分析。5种模型OR值与95%CI均大于1,有显著性意义(P < 0.05),显示出MTHFR C677T基因多态性与出血性脑卒中风险存在相关性,T等位基因携带者患出血性脑卒中的风险比CC纯合子的患病风险提高了39%,CT+TT基因型相较于CC基因型出血性脑卒中风险提高了46%,TT基因型相较于CC+CT基因型出血性脑卒中风险提高了54%,CT基因型相较于CC基因型出血性脑卒中风险提高了31%,TT基因型相较于CC基因型出血性脑卒中风险提高了78%。仅展示等位基因模型森林图,如图 4。"
2.2.2 MTHFR基因A1298C位点多态性与出血性脑卒中风险 建立下述遗传模型分别进行分析,等位基因模型C vs. A,显性模型(CC+AC) vs. AA,隐性模型CC vs. (AC+AA),共显性杂合子模型AC vs. AA,共显性纯合子模型CC vs. AA。如表5所示,除隐性模型异质性较大采用随机效应模型外(I2≥50%,P < 0.05),其他遗传模型异质性均较小,采用固定效应模型分析(I2 < 50%,P > 0.05)。5种模型OR值的可信区间均包含1,OR值无显著性意义(P > 0.05),显示出MTHFR基因A1298C位点多态性与出血性脑卒中风险无明显统计学相关性。仅展示等位基因模型森林图,如图5。"
(1)依据地理区域分组分析结果表明,在亚洲地区的研究中,5种遗传模型OR值和95%CI均大于1,表现出 MTHFR C677T基因多态性与出血性脑卒中有明显的统计学相关性,但是各研究间异质性仍较大;与之不同的是在欧洲和非洲地区研究的异质性较小,MTHFR C677T基因多态性与出血性脑卒中无明显的统计学相关性,但是值得注意的是亚洲区域的研究纳入的样本量较多,欧洲和非洲纳入的样本量较少。 (2)依据患者平均年龄分组分析结果表明,在患者平均年龄> 60岁的人群中,5种遗传模型OR值和95%CI均大于1,表现出 MTHFR C677T基因多态性与出血性脑卒中有明显的统计学相关性,但是各研究间异质性仍较大;在≤10岁的人群的研究中,研究异质性较小且MTHFR C677T基因多态性与出血性脑卒中无明显的统计学相关性,但是样本量较少,且均为欧洲的研究。 (3)依据研究所纳入的患者样本量分组。在≥100例患者的研究中,尽管各研究间异质性较大,但是5种遗传模型均表现出 MTHFR基因C677T位点多态性与出血性脑卒中有明显的统计学相关性;在< 100例患者的研究中,共显性杂合子模型无显著性意义,其他4种遗传模型均有显著性意义,其中显性遗传模型和隐性遗传模型的研究间异质性明显减小。 (4)依据是否仅研究出血性脑卒中的脑出血进行分组,MTHFR C677T基因多态性与脑出血以及出血性脑卒中(脑出血+蛛网膜下腔出血)均有明显的统计学相关性,OR值和95%CI均大于1,除隐性遗传模型各研究间异质性较低,其他4种遗传模型异质性仍较高。 (5)依据纳入研究是否确保年龄和性别混杂因素在病例组和对照组中无统计学差异而进行亚组分析。结果表明,相较于未控制年龄和性别因素的研究,控制这两种因素后,5种遗传模型的OR值和95%CI均大于1,表现出 MTHFR C677T基因多态性与出血性脑卒中有明显的统计学相关性,且隐性遗传模型的研究间异质性明显降低。 亚组分析结果见表7。因此,MTHFR C677T基因研究多态性与出血性脑卒中的相关性研究间存在较大异质性的原因是多因素的,且对不同遗传模型的影响不同,亚组分析一定程度上降低了异质性。"
(1)依据地理区域分组,无统计学相关性。 (2)依据患者平均年龄分组。在≤10岁的人群中,AC基因型增加了出血性脑卒中风险(OR=1.64,95%CI:1.19-2.26)。 (3)依据研究所纳入的患者样本量分组。对样本量≥100例的研究中,表明AC基因型增加了出血性脑卒中风险(OR=1.41,95%CI:1.08-1.85)。 (4)依据是否仅研究出血性脑卒中的脑出血进行分组,在仅对脑出血研究中,携带C等位基因增加了脑出血的风险(OR=1.64,95%CI:1.19-2.26)。 (5)依据纳入研究是否确保年龄和性别混杂因素在病例组和对照组中无统计学差异而进行亚组分析。缺乏对年龄和性别匹配的研究显示携带C等位基因增加了出血性脑卒中风险(OR=1.35,95%CI:1.05-1.72)。 亚组分析后各组的异质性明显降低,但是样本量也减少,因此结论的可靠性降低。 2.4 敏感性分析结果 2.4.1 MTHFR C677T基因多态性与出血性脑卒中关联敏感性分析结果 此5种遗传模型分别进行敏感性分析,依次剔除一项文献研究,结果表明对最终的合并效应量OR值和95%CI范围影响不大,在可接受范围内,均大于1,说明该研究结果较稳定,MTHFR C677T基因多态性与出血性脑卒中有明显的统计学相关性,见图6。"
2.4.2 MTHFR A1298C基因多态性与出血性脑卒中关联敏感性分析结果 此 5种遗传模型分别进行敏感性分析,依次剔除一项文献研究。 (1)在等位基因遗传模型(C vs. A)中,当剔除ABIDI等[30]文献时,OR值和可信区间下限均大于1,出现明显波动,可见这篇文献具有较大的异质性,查阅该文献,发现该研究病例组与对照组的年龄差别大,分别是(43.3±15.2)岁和(54.5±8.8)岁,且性别比例差异较大,两组间其他混杂因素控制亦不明确,可能是异质性来源的原因。 (2)在显性遗传模型(AC+CC) vs. AA中,当剔除Tsymbaliuk等[38]文献时,OR值和可信区间下限均大于1,出现明显波动,可见这篇文献具有较大的异质性,查阅该文献,发现缺乏出血性脑卒中病例患者的一般基线资料,尚无法确定与对照组具备良好的可比性。 (3)在隐性遗传模型CC vs. (AA+AC)中,任意剔除一篇文献,OR值和可信区间波动在可接受范围内,结果较稳定。 (4)在共显性杂合子模型AC vs. AA中,当剔除TSYMBALIUK等[38]文献时,OR值和可信区间下限均大于1,出现明显波动,原因可能同(2)中所述。 (5)在共显性纯合子模型(CC vs. AA)中,当剔除ABIDI等[30]文献时,OR值和可信区间下限均大于1,出现明显波动,可见这篇文献具有较大的异质性,原因可能同(1)所阐述。 因此,相关研究较少,携带C等位基因以及CC基因型与出血性脑卒中的相关性仍待进一步研究,尚不能认为MTHFR A1298C基因多态性与出血性脑卒中存在相关性。敏感性分析结果见图7。"
2.6 阳性结果的可信度分析 依据上述有显著性意义的结果的OR值和95%CI,计算对应模型的FPRP值,结果如表11所示。以FPRP值< 0.2为标准判断关联性可靠的标准。整体分析C677T位点,除CT vs. CC模型不满足外,其他模型均满足标准,整体说明C677T位点多态性与出血性脑卒中的关联结果可靠。进行亚组分析后,在亚洲人群中T vs. C和TT vs. (CT+CC)满足标准,在患者平均年龄> 60岁中TT vs. (CT+CC)满足标准,在患者样本量< 100例中(TT+CT) vs. CC满足标准,在匹配因素控制(是)中T vs. C和TT vs. (CT+CC)满足标准。由于亚组分析使得样本量减少,导致部分模型的假阳性概率提高,但是各亚组下均有满足条件的模型,因而提示C677T位点多态性与出血性脑卒中的关联结果较可靠。亚组分析中有显著性意义的A1298C位点多态性与出血性脑卒中的关联结果不满足标准,假阳性的可能性较大,结果不可靠。"
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