ALL患儿MTHFD1基因多态性与大剂量甲氨蝶呤血药浓度及不良反应的关系  

Association between MTHFD1 genetic polymorphism,methotrexate plasma concentration at large dose and adverse reactions in ALL children

作　　者：朱影[1,2] 郑恒[1] 刘璐[1] 曹舒雯[1] 魏盈盈[1] 刘东[1] 杜光[1] 丁水平[1] 楼一层[2] 丁玉峰[1] 

机构地区：[1]华中科技大学同济医学院附属同济医院,湖北武汉430030 [2]武汉理工大学化学化工与生命科学学院,湖北武汉430070

出　　处：《中国医院药学杂志》2015年第20期1869-1873,共5页Chinese Journal of Hospital Pharmacy

基　　金：国家科技部重大新药创制专项(编号:2012ZX09303018);湖北省自然基金(编号:2014CKB515);华中科技大学同济医学院附属同济医院内部科研基金项目(编号:2014YJJ026)

摘　　要：目的:探讨亚甲基四氢叶酸脱氢酶1(MTHFD1)G1958A基因多态性与急性淋巴细胞白血病(ALL)患儿使用大剂量甲氨蝶呤(HD-MTX)化疗期间的MTX血药浓度及不良反应的关系。方法:收集70例急性淋巴细胞白血病患儿外周血,提取DNA,采用PCR技术和直接测序的方法分析MTHFD1基因的基因型;采用酶放大免疫法(EMIT)测定MTX给药后48 h的血药浓度;收集患者HD-MTX化疗期间的临床资料,统计不良反应相关信息,对化疗不良反应进行分级。分析MTHFD1基因多态性与MTX血药浓度及不良反应的关系。结果:MTHFD1 G1958A基因位点存在多态性,70例ALL患儿中GG、AG和AA基因型的分布频率分别为41.43%,52.86%,5.71%;G和A等位基因的分布频率分别为67.86%和32.14%。携带野生基因型(GG)ALL患儿的48hC/D值高于突变型基因型(GA+AA)携带者;携带野生基因型(GG)ALL患儿的骨髓抑制和肝脏损害不良反应发生率高于携带突变基因型(GA+AA)ALL患儿。由于个体间差异大,上述差异均无统计学意义(P>0.05)。结论:影响MTX的体内代谢和不良反应的因素复杂,MTHFD1 G1958A多态性尚不能作为ALL患儿HDMTX化疗所致骨髓移植和肝脏损害不良反应和预测MTX体内排泄的有效预测指标。OBJECTIVE To investigate association between genetic polymorphism of methylenetetrahydrofolate dehydrogenase1（MTHFD1）G1958A genotype and methotrexate plasma concentration and adverse reactions during high dose methotrexate（HD-MTX）chemotherapy in children with acute lymphoblastic leukemia（ALL）.METHODS A total of 70 peripheral blood samples were obtained from children with ALL for extracting genome DNA.Gene polymorphism of MTHFD1 G1958 A locus was examined by using PCR technology and direct sequencing method.Enzyme-amplified immunoassay（EMIT）was employed to determine plasma concentration of MTX in48 h.Clinical data of patients were collected during HD-MTX chemotherapy,related adverse reaction information and classified adverse reaction of chemotherapy were acquired.Association between MTHFD1 genotype and MTX plasma concentration and adverse reactions were investigated.RESULTS Genetic polymorphism existed at SNP,and in70 children with ALL,percentages of GG,GA and AA genotype were 41.43%,52.86% and 5.71%,respectively.Frequencies of G and A alleles were 67.86%and 32.14%,respectively.Compared with wild genotype（GG）carriers,mutant genotype（GA＋TT）carriers had lower C/D ratios of MTX in48 h,and lower incidence of liver damage and myelosuppression.Due to high inter-individual variation,differences above were not significant（P〉0.05）.CONCLUSION Multiple factors affect pharmacokinetics and toxicity of MTX.This study suggests that MTHFD1 gene 1958 polymorphism can not serve as predictor of HDMTX-induced myelosuppression and liver damage in children with ALL,neither predictor of in vivo MTX excretion.

关 键 词：儿童急性淋巴细胞白血病 亚甲基四氢叶酸脱氢酶1 基因多态性 甲氨蝶呤 血药浓度 骨髓抑制 肝脏损害 

分 类 号：R969.1[医药卫生—药理学]