MTHFR C677T基因多态性与儿童急性淋巴细胞白血病大剂量甲氨蝶呤治疗不良反应的相关性研究

Relationship between MTHFR Gene Polymorphism(C677T)and Adverse R eactions of High-Dose Methotrexate in Pediatric Patients with Acute Lymphoblastic Leukemia

目的:研究亚甲基四氢叶酸还原酶(MTHFR)C677T基因多态性对儿童急性淋巴细胞白血病(ALL)大剂量甲氨蝶呤(MTX)治疗后不良反应的影响。方法:收集中山大学孙逸仙纪念医院儿科2018年11月至2020年10月收治的69例ALL患儿的临床资料,分离患儿外周血白细胞,用数字荧光分子杂交测序法进行MTHFR基因分型;观察大剂量MTX治疗后的不良反应,同时监测MTX血药浓度,分析MTHFR基因多态性对治疗不良反应及MTX血药浓度的影响。结果:中高危ALL患儿中,与野生组(CC基因型)比较,MTHFR C677T突变组(CT+TT基因型)患儿发生白细胞减少(OR=2.38)、中性粒细胞减少(OR=2.2)、血红蛋白减少(OR=1.83)、肝功能损害的风险高(OR=1.98)。然而,MTHFR C677T突变组与野生组在24、48及72 h的MTX血药浓度无明显差异。多因素分析结果显示,MTX血药浓度(48 h)、ALL临床危险度分级、MTHFR C677T基因多态性是影响大剂量MTX治疗不良反应的危险因素。结论:MTHFR C677T基因突变与ALL患儿大剂量MTX治疗后骨髓抑制和肝功能损害存在相关性。

Objective:To explore the effects of methylenetetrahydrofolate reductase(MTHFR)C677T gene polymorphism on the adverse reactions of high-dose methotrexate(MTX)in pediatric patients with acute lymphoblastic leukemia(ALL).Methods:A total of 69 children with ALL admitted to the department of Pediatrics of Sun Yat-sen Memorial Hospital of Sun Yat-sen University from November 2018 to October 2020 were included in this study.The clinical data of the children were collected,leukocytes were isolated from their peripheral blood,and MTHFR genotyping was performed by digital fluorescence molecular hybridization techniques.The adverse reactions and plasma drug concentration of MTX were monitored during the chemotherapy.Moreover,the effect of MTHFR gene polymorphism on MTX adverse reactions and plasma drug concentration were analyzed..Results:Among the middle and high risk children,compared with the wildtype group(CC genotype),patients with MTHFR C677T mutations(CT+TT genotypes)had a higher risk of leukopenia(OR=2.38),neutropenia(OR=2.2),anemia(OR=1.83)and hepatoxicity(OR=1.98).However,no significant difference was found in the MTX plasma concentration between the MTHFR C677T mutantion group and the wildtype group at different timepoints(24 h,48 h and 72 h).Multivariate analysis revealed that the plasma concentration of MTX(48 h),clinical risk level of ALL and MTHFR C67T gene.polymorphism were independent factors for the adverse reactions of high-dose MTX.Conclusion:The MTHFR C677T mutations may be associated with myelosuppression and hepatotoxicity in children with ALL after high-dose MTX treatment.