血液恶性肿瘤患者中MTHFR基因多态性与大剂量甲氨蝶呤血液毒性相关性的Meta分析

Hematotoxicity Correlation of MTHFR Gene Polymorphism with High-dose of Methotrexate in Hematological Neoplasm Patients:A Meta-analysis

目的:系统评价血液恶性肿瘤患者中亚甲基四氢叶酸还原酶(MTHFR)C677T及A1298C多态性与大剂量甲氨蝶呤(HDMTX)血液系统不良事件的相关性。方法:系统检索Medline、Embase、Clinical Trials.gov、中国学术期刊网络出版总库、万方数据库、中国生物医学文献数据库,收集采用HDMTX治疗血液恶性肿瘤涉及MTHFR C677T及A1298C基因多态性的队列研究,时限均为自建库起至2018年3月。对符合纳入标准的文献进行资料提取,并采用纽卡斯尔-渥太华量表进行质量评价后,应用Rev Man 5.3软件对不同遗传模型下HDMTX血液系统不良事件进行Meta分析。结果:共纳入25项队列研究,其中23项研究关注MTHFR C677T位点(1 858例患者)、16项研究关注MTHFR A1298C位点(1 088例患者)。Meta分析结果表明,MTHFR C677T突变型显著增加了血液毒性[TT/CT vs. CC:OR=1.57,95%CI(1.12,2.20),P=0.009;TT vs. CT/CC:OR=2.19,95%CI(1.49,3.23),P<0.001;T vs. C:OR=1.34,95%CI(1.03,1.74),P=0.03]、严重血液毒性[TT/CT vs. CC:OR=2.33,95%CI(1.43,3.81),P<0.001]的发生风险,具体包括增加了白细胞减少[TT/CT vs. CC:OR=1.37,95%CI(1.02,1.82),P=0.03]、严重白细胞减少[TT/CT vs. CC:OR=1.63,95%CI(1.03,2.56),P=0.04]、严重粒细胞减少[TT/CT vs. CC:OR=2.26,95%CI(1.50,3.39),P<0.001]的发生风险;MTHFR A1298C突变型显著降低了严重血液毒性[CC/AC vs. AA:OR=0.17,95%CI(0.04,0.76),P=0.02]的发生风险,具体包括降低了白细胞减少[CC/AC vs. AA:OR=0.68,95%CI(0.48,0.97),P=0.03;CC vs. AC/AA:OR=0.28,95%CI(0.14,0.59),P<0.001]、严重白细胞减少[CC/AC vs. AA:OR=0.43,95%CI(0.19,0.97),P=0.04]的发生风险。结论:在血液恶性肿瘤患者中,MTHFR C677T突变型可能增加HDMTX血液毒性发生风险,包括白细胞减少以及粒细胞减少;而MTHFR A1298C突变型则可能降低HDMTX血液毒性发生风险,包括白细胞减少。

OBJECTIVE:To systematically evaluate the correlation of methylenetetrahydrofolate reductase(MTHFR)C677T and A1298C gene polymorphisms with blood system adverse events induced by high-dose of methotrexate(HDMTX).METHODS:Retrieved from Medline,Embase,Clinical Trials.gov,CNKI,Wanfang database,CBM,cohort studies about MTHFR gene polymorphism in hematological neoplasm treated by HDMTX were collected from inceptions to March 2018.After data extraction of included literatures,quality evaluation with Newcastle Ottawa scale,Meta-analysis was performed for adverse events of blood system induced by HDMTX in different genetic models with Rev Man 5.3 software.RESULTS:Totally 25 cohort studies were included,23 studies of which were related to MTHFR C677T site(including 1858 patients)and 16 studies related to MTHFR A1298C site(including 1088 patients).Results of Meta-analysis showed that MTHFR C677T mutation type significantly increased the risk of hematotoxicity[TT/CT vs.CC:OR=1.57,95%CI(1.12,2.20),P=0.009;TT vs.CT/CC:OR=2.19,95%CI(1.49,3.23),P<0.001;T vs.C:OR=1.34,95%CI(1.03,1.74),P=0.03]and severe hematotoxicity[TT/CT vs.CC:OR=2.33,95%CI(1.43,3.81),P<0.001],including leukopenia[TT/CT vs.CC:OR=1.37,95%CI(1.02,1.82),P=0.03],severe leukopenia[TT/CT vs.CC:OR=1.63,95%CI(1.03,2.56),P=0.04],severe granulopenia[TT/CT vs.CC:OR=2.26,95%CI(1.50,3.39),P<0.001].The mutation genotypes of MTHFR A1298C significantly decreased the risk of severe hematotoxicity[CC/AC vs.AA:OR=0.17,95%CI(0.04,0.76),P=0.02],including leukopenia[CC/AC vs.AA:OR=0.68,95%CI(0.48,0.97),P=0.03;CC vs.AC/AA:OR=0.28,95%CI(0.14,0.59),P<0.001]and severe leukopenia[CC/AC vs.AA:OR=0.43,95%CI(0.19,0.97),P=0.04].CONCLUSIONS:Among patients with hematological neoplasms,MTHFR C677T mutation may significantly increase the risk of hematotoxicity by HDMTX including the risk of leukopenia and granulopenia;while MTHFR A1298C may reduce the risk of hematotoxicity by HDMTX,including the risk of leukopenia.