MTHFR基因多态性对大剂量甲氨蝶呤化疗后患儿血药浓度及药物不良反应的影响

Effect of MTHFR Gene Polymorphism on Plasma Concentration and Adverse Drug Reactions in Children with High Dose Methotrexate Chemotherapy

目的:探讨亚甲基四氢叶酸还原酶(MTHFR)基因多态性与儿童急性淋巴细胞白血病(ALL)大剂量甲氨蝶呤(HD-MTX)化疗后甲氨蝶呤(MTX)血药浓度及药物不良反应的关系。方法:收集ALL患儿血样77例,采用聚合链式反应技术扩增后测序分析MTHFR A1298C、MTHFR C677T基因分型,采用酶放大免疫分析法测定患儿MTX用药后48 h血药浓度,收集患儿HD-MTX用药期间相关临床资料及用药后药物不良反应信息。采用方差分析、Logistic回归分析MTHFR基因多态性与HD-MTX化疗后药物不良反应的关系。结果:77例ALL患儿中,MTHFR A1298C基因AA型、AC型、CC型患儿分别为55例(71.43%)、20例(25.97%)、2例(2.60%);MTHFR C677T基因CC型、CT型、TT型患儿分别为8例(10.39%)、43例(55.84%)、26例(33.77%)。不同MTHFR A1298C基因型患儿中性粒细胞减少、血红蛋白降低、黏膜损害、肝脏损害等药物不良反应的发生风险无统计学差异,而MTHFR A1298C AA基因型携带者发生血小板减少的风险增加了2.10倍(OR=2.10,95%Cl:0.23~19.08,P<0.05),胃肠道不良反应发生率增高,具有统计学差异(P<0.05);与CT型、TT型携带者相比,MTHFR C677T CC基因型携带者血小板减少、血红蛋白降低和黏膜损害的发生率升高,具有统计学差异(P<0.05);MTHFR基因多态性与MTX用药后48 h血药浓度变化无相关性。结论:MTHFR A1298C基因多态性与ALL患儿HD-MTX化疗后血小板减少、胃肠道反应的发生有关;MTHFR C677T基因多态性与ALL患儿HD-MTX化疗后血小板减少、血红蛋白降低及黏膜损害的发生存在一定的相关性。

Objective:To investigate the relationship between MTHFR gene polymorphism and methotrexate(MTX)blood concentration and adverse drug reactions after high dose methotrexate(HD-MTX)chemotherapy in children with acute lymphocytic leukemia(ALL).Methods:77 children with ALL were collected,and the genotypes of MTHFR A1298C and MTHFR C677T were analyzed by polymerization chain reaction amplification.Enzyme amplification and immunoassay was used to determine the blood concentration 48 h after MTX treatment,and the relevant clinical data and adverse drug reactions during the treatment with HD-MTX were collected.The relationship between MTHFR gene polymorphism and adverse drug reactions after HD-MTX chemotherapy was analyzed by analysis of variance and Logistic regression.Results:Among 77 children with ALL,children with AA,AC and CC of MTHFR A1298C were 55(71.43%),20(25.97%)and 2(2.60%)respectively.children with CC,CT and TT types of MTHFR C677T were 8(10.39%),43(55.84%)and 26(33.77%)respectively.The risk of adverse drug reactions has no significant difference for children with different MTHFR A1298C gene type,such as neutropenia,hemoglobin reduction,mucosal damage,and hepatorenal toxicity,while MTHFR A1298C AA genotype carriers had a 2.10-fold increased risk of thrombocytopenia(OR=2.10,95%Cl:0.23~19.08,P<0.05),the incidence of gastrointestinal adverse reactions increased,with statistical difference(P<0.05).Compared with CT and TT carriers,MTHFR C677T CC carriers had higher incidence of thrombocytopenia,decreased hemoglobin and mucosal damage,with statistical differences(P<0.05).There was no correlation between MTHFR gene polymorphism and the change of serum concentration 48 h after MTX administration.Conclusion:MTHFR A1298C gene polymorphism is related to thrombocytopenia and gastrointestinal reactions after HD-MTX chemotherapy in ALL children,and MTHFR C677T gene polymorphism is related to thrombocytopenia,hemoglobin reduction and mucosal damage after HD-MTX chemotherapy in ALL children.