亚甲基四氢叶酸还原酶基因多态性与急性淋巴细胞白血病患者甲氨蝶呤化疗药物不良反应的相关性研究

Association of methylenetetrahydrofolate reductase polymorphism and adverse reaction of methotrexate chemotherapy in acute lymphocytic leukemia

目的探讨急性淋巴细胞白血病(ALL)患者的亚甲基四氢叶酸还原酶(MTHFR)C677T基因多态性与大剂量甲氨蝶呤(HD-MTX)化疗药物不良反应的相关性。方法收集93例ALL患者血样,用试剂盒法提取血液DNA,用聚合酶链式反应-芯片杂交技术检测MTHFR C677T基因多态性,用酶放大免疫分析法(EMIT)测定患者MTX血药浓度,收集患者HD-MTX化疗期间的临床资料,并观察记录患者HD-MTX化疗后相关药物不良反应。结合MTHFR C677T基因分型结果,用方差分析、非线性Logistic回归分析MTHFR C677T基因多态性与HD-MTX化疗后药物不良反应的关系。结果 MTHFR C677T各基因型间口腔黏膜损害的发生率差异有统计学意义(P<0.05),MTHFR 677CT/TT基因型者发生口腔黏膜损害的风险较CC基因型者显著性增高,CT基因型者发生口腔黏膜损伤的风险是CC基因型者的2.81倍(OR=2.81,95%CI:1.06~7.40,P<0.05),TT型是CC型的5.53倍(OR=5.53,95%CI:1.58~19.27,P<0.05)。MTHFR C677T各基因型间Ⅱ级以上骨髓抑制的发生率差异有统计学意义(P<0.05),TT型发生Ⅱ级以上骨髓抑制的风险是CC型的3.75倍(OR=3.75,95%CI:1.14~12.40,P<0.05);MTHFR C677T各基因型在HD-MTX给药后48 h的血药浓度差异有统计学意义(P<0.05)。结论 MTHFR C677T基因多态性影响ALL患者HD-MTX化疗期间MTX血药浓度,与口腔黏膜损害、骨髓抑制存在一定相关性。

Objective To study the association of methylenetetrahydrofo- late reductase （MTHFR） gene C677 T polymorphism and adverse reaction of high - dose methotrexate （ HD - MTX） chemotherapy in acute lympho- cytic leukemia（ALL）. Methods Ninety - three blood samples of ALL patients were collected. Kit assay was used to study the DNA by blood samples. Polymerase chain reaction -microarray hybridization technology was used to detect the polymorphism of MTHFR C677T. Enzyme multiplied immunoassay （EMIT） technique was used to monitor dynamic se-rum concentration of patients. Clinical data of the ALL patients were collected and adverse effect were recorded to observe the incidence of adverse effect during the chemotherapy of HD - MTX. ANOVA and Logis- tic regression were used to analyze the association of polymorphism in MTHFR C677T gene and adverse reaction by HD -MTX. Results Therewas significant difference between MTHFR C677 T and mucositis. The risk of mucositis was higher in carriers of MTHFR 677CT ＋ TY genotype as compared with patients with 677CC genotype, CT genotype was higher above grade 2. 81 （ OR = 2. 81, 95% CI ： 1.06 - 7.40, P 〈 0. 05 ） as compared with CC genotype, and tit genotype was higher above grade 5.53 （OR = 5.53, 95% CI：I. 58 - 19.27,P 〈 0. 05）. The incidence of Ⅱ myelosuppression in Tr genotype was higher above grade 3.75（OR =3.75, 95%CI： 1.13 -12.40, P 〈0. 05） as compared with CC genotype. There was significant difference about the dynamic serum concentration of 48h after HD - MTX chemotherapy among the MTHFR C677 T genotype （P 〈 0. 05 ）. Conclusion The MTHFR C677 T polymorphism may have influence on the dynamie serum concentration of MTX. There was some relevance between MTHFR C677 T polymorphism and adverse reactions （mucositis and Myelosuppression） after chemotherapy with HD -MTX.