亚甲基四氢叶酸还原酶基因多态性与儿童甲氨蝶呤化疗血药浓度及药物不良反应的关系

Association between methylenetetrahydrofolate reductase polymorphism,methotrexate plasma concentration and adverse drug reactions of methotrexate chemotherapy in children with acute lymphoblastic leukemia

目的研究亚甲基四氢叶酸还原酶(MTHFR)基因C677T位点遗传多态性与急性淋巴细胞白血病(ALL)儿童使用大剂量甲氨蝶呤(HD-MTX)化疗期间血药浓度及药物不良反应的关系。方法收集ALL患儿血样61例,采用试剂盒提取血液DNA,用聚合酶链反应-基因芯片杂交技术检测MTHFR C677T多态性,用酶放大免疫分析法测定MTX给药后的血药浓度。记录患儿HD-MTX化疗后相关药物不良反应,分析MTHFR C677T基因多态性与ALL儿童HD-MTX化疗后MTX血药浓度及药物不良反应的关系。结果MTHFR C677T在汉族与维吾尔族患儿中CC型分布频率分别为18.2%和44.0%,TT型分布频率分别为36.4%和12.0%,差异均有统计学意义(均P<0.05)。MTHFR C677T CC型与TT型的48 h的血药浓度最大值分别为0.75和1.31μmol·L^-1,差异有统计学意义(P<0.05)。MTHFR C677T CT型与TT型的72 h的血药浓度最大值分别为0和0.17μmol·L^-1,差异有统计学意义(P<0.05)。MTHFR C677T TT型和CC型的Ⅰ级以上骨髓抑制发生率分别33.30%和23.10%,Ⅱ级以上白细胞减少发生率分别为45.50%和22.70%,差异均有统计学意义(均P<0.05)。结论MTHFR C677T基因多态性影响ALL患儿MTX血药浓度,与HD-MTX化疗后骨髓抑制、白细胞减少存在一定相关性。

Objective To study the association between methylenetetrahydrofolate reductase(MTHFR)gene C677T polymorphism and methotrexate plasma concentration and adverse drug reaction during high-dose methotrexate(HD-MTX)chemotherapy in children with acute lymphoblastic leukemia(ALL).Methods Sixty-one blood samples of children with ALL were collected.Kit assay was used to study the DNA of blood samples.Polymerase chain reaction-microarray hybridization technology was used to detect the polymorphism of MTHFR C677T.Enzyme multiplied immunoassay technique was employed to determine the plasma concentration of MTX in 24 h,48 h and 72 h after MTX administration.Adverse drug reactions after HD-MTX chemotherapy in children were recorded,and the association between MTHFR C677 genotype and MTX plasma concentration and adverse drug reaction were investigated.Results The distribution frequencies of MTHFR C677T CC genotype were 18.2%and 44.0%,and TT genotype were 36.4%and 12.0%in Han and Uyghur ALL children,with statistically significant difference between the two groups(all P<0.05).The maximum blood concentrations of methotrexate in the children with MTHFR C677T CC type and TT type at 48h were 0.75 and 1.31μmol·L^-1,with statistically significant differences(P<0.05).The maximum blood concentration s of methotrexate in the children with MTHFR C677T CC type and TT type at 72 h were 0 and 0.17μmol·L^-1,with statistically significant differences(P<0.05).The incidences of myelosuppression above gradeⅠin TT type and CC type were 33.30%and 23.10%,and the incidences of leucocyte reduction above gradeⅡin TT type and CC type were 45.50%and 22.70%,with statistically significant differences between them(all P<0.05).Conclusion The polymorphism of MTHFR C677T gene affects the concentration of MTX in children with ALL,which is correlated with bone marrow suppression and leukopenia after HD-MTX chemotherapy.