MTHFR及ABCB1基因多态性与急性淋巴细胞白血病患儿大剂量甲氨蝶呤药物不良反应关系  

Retrospective cohort study on the relationship between MTHFR and ABCB1 gene polymorphisms and high-dose methotrexate toxicity in children with acute lymphoblastic leukemia

作　　者：徐蕊 李静[3] 胡玉 麦吾菊丹·阿力甫 张瑞[1] 姜雯[1] 孙璇[1] 王琳 赵军[3,4] XU Rui;LI Jing;HU Yu;MAI Wu-jü-dan·A Li-fu;ZHANG Rui;JIANG Wen;SUN Xuan;WANG Lin;ZHAO Jun(Department of Pharmacy,The SixthhAffiliated Hospital of Xinjiang Medical University,Urumqi 830002,XinjiangUygurAutonomous Region,China;Department of General Medicine,The SixthhAffiliated Hospital of Xinjiang Medical University,Urumqi 830002,XinjiangUygurAutonomous Region,China;Department of Pharmacy,The First Affiliated Hospital of Xinjiang Medical University,Urumqi 830054,Xinjiang Uygur Autonomous Region,China;Xinjiang Key Laboratory of Clinical Drug Research,Urumqi 830054,XinjianggUygurAutonomous Region,China)

机构地区：[1]新疆医科大学第六附属医院药学部,新疆维吾尔自治区乌鲁木齐830002 [2]新疆医科大学第六附属医院全科医学科,新疆维吾尔自治区乌鲁木齐830002 [3]新疆医科大学第一附属医院药学部,新疆维吾尔自治区乌鲁木齐830054 [4]新疆药物临床研究重点实验室,新疆维吾尔自治区乌鲁木齐830054

出　　处：《中国临床药理学杂志》2024年第13期1963-1967,共5页The Chinese Journal of Clinical Pharmacology

基　　金：国家重点研发计划课题基金资助项目(2017YFC0910001);天山英才"医药卫生高层次人才培养计划基金资助项目(TSYC202301A051);新疆医科大学第六附属医院临床药学重点专科基金资助项目(202401)。

摘　　要：目的确定亚甲基四氢叶酸还原酶(MTHFR)C677T、A1298C及多药耐药1(ABCB1)C3435T基因多态性与急性淋巴细胞白血病(ALL)患儿大剂量甲氨蝶呤(HD-MTX)药物不良反应关系。方法收集用HD-MTX化疗的ALL患儿血样,用测序法检测MTHFR C677T、A1298C和ABCB1 C3435T基因多态性,根据抗癌药物常见药物不良反应分级标准统一评价MTX化疗后的药物不良反应,统计分析MTHFR C677T、A1298C及ABCB1 C3435T基因多态性与HD-MTX药物不良反应的关系。结果MTHFR A1298C AC+CC型肝功能损伤(2级)风险高于AA型[比值比(OR)=2.350,95%置信区间(CI)=1.038~5.320,(P<0.05)],未发现MTHFR A1298C与骨髓抑制、黏膜损伤、胃肠道反应及急性肾损伤有相关性(均P>0.05)。ABCB1 C3435T CT型肝功能损伤(2级)风险高于TT型(OR 5.161,95%CI=1.371~19.424,P<0.05),ABCB1 C3435T CC+CT型肝功能损伤(2级)风险高于TT型(OR 4.231,95%CI=1.165~15.362,P<0.05),未发现ABCB1 C3435T与骨髓抑制、黏膜损伤、胃肠道反应及急性肾损伤有相关性(均P>0.05)。未发现MTHFR C677T与HD-MTX药物不良反应有相关性(均P>0.05)。结论在用HD-MTX治疗ALL时,可通过检测MTHFR A1298C及ABCB1 C3435T基因型来预测药物不良反应,从而实施更加科学的个体化用药。Objective To determine the relationship between methylenetetrahydrofolate reductase(MTHFR)C677T,A1298C and multidrug resistance 1(ABCB1)C3435T gene polymorphisms and the adverse reactions of high-dose methotrexate(HD-MTX)in children with acute lymphoblastic leukemia(ALL).Methods Blood samples of ALL children treated with HD-MTX chemotherapy were collected,and the polymorphic polymorphism of MTHFR C677T,A1298C and ABCB1C3435T genes were detected by sequencing method.The adverse drug reactions after MTX chemotherapy were evaluated according to the common adverse drug reaction grading criteria.The relationship between MTHFR C677T,A1298C and ABCB1 C3435T gene polymorphisms and HD-MTX adverse drug reactions was analyzed.Results The risk of MTHFR A1298C AC+CC type hepatic injury(grade 2)was higher than AA type[odds ratio(OR)2.350,95%confidence interval(CI)=1.038-5.320,P<0.05],no correlations were found between MTHFR A1298 C and myelosuppression,mucositis,gastrointestinal reaction and acute renal impair(all P>0.05).ABCB1 C3435T CT type hepatic injury(grade 2)was higher than TT type(OR 5.161,95%CI 1.371-19.424,P<0.05),ABCB1 C3435T CC+CT type hepatic injury(grade 2)was higher than TT type(OR 4.231,95%CI 1.165-15.362,P<0.05);no correlations were found between ABCB1 C3435T and myclosuppression,mucositis,gastrointestinal reaction and acute renal impair(all P>0.05).No correlations wre found between MTHFR C677T and HD-MTX adverse drug reactions(all P>0.05).Conclusion When treating ALL with HD-MTX,adverse drug reactions can be predicted by detecting MTHFR A1298 C and ABCB1 C3435T genotypes,so as to implement more scientific individualized medication.

关 键 词：急性淋巴细胞白血病 儿童 大剂量甲氨蝶呤 亚甲基四氢叶酸还原酶 多药耐药1 药物不良反应 

分 类 号：R979.1[医药卫生—药品]