儿童急性淋巴细胞白血病ABCB1、ABCC4和SLCO1B1多态性与大剂量MTX血药浓度及不良反应的相关性

Association of ABCB1,ABCC4 and SLCO1B1 polymorphisms with high dose-MTX blood concentration and adverse events in childhood acute lymphoblastic leukemia

目的探讨三磷酸腺苷结合盒转运体B1、C4(ABCB1、ABCC4)和溶质载体有机阴离子转运体(SLCO1B1)基因多态性与急性淋巴细胞白血病(ALL)患儿甲氨蝶呤(MTX)血药浓度及大剂量甲氨蝶呤(HD-MTX)所致药物不良反应(AE)的相关性。方法收集2018年1月至2019年12月首都医科大学附属北京儿童医院收治的接受HD-MTX治疗的ALL住院患儿275例;用化学发光微粒子免疫分析(CMIA)检测给药后45 h时的血药浓度。基于延伸连接的多重探针扩增(MELPA)技术通过核酸飞行质谱(MALDI-TOF MS)检测ABCB1 rs1045642位点、ABCC4 rs7317112位点、SLCO1B1 rs11045879和rs10841753位点的单核苷酸多态性(SNP)。同时,观察记录化疗后不良反应,包括肝功能损害、胃肠道反应、黏膜炎、骨髓抑制、心肌损伤等。分析这些基因SNP位点多态性与MTX血药浓度及AE的相关性。结果各基因型频率均符合Hardy-Weinberg平衡(P>0.05)。ABCC4 rs7317112位点和SLCO1B1 rs11045879位点多态性与HD-MTX化疗开始后45 h的血药浓度之间有相关性(P<0.05)。ABCC4 rs7317112的AA/AG型和SLCO1B1 rs11045879的TT/TC型易出现MTX排泄延迟(P<0.05)。结论ABCC4 rs7317112位点和SLCO1B1 rs11045879位点可以作为重要的基因标志物辅助儿童ALL患者HD-MTX个体化用药。

Objective To investigate potential relationship between gene polymorphisms of ATP-binding cassette B1,C4(ABCB1,ABCC4)and solute carrier organic anion transporter 1B1 gene(SLCO1B1)with methotrexate(MTX)blood drug concentration and high dose-MTX(HD-MTX)-related adverse events(AEs)in childhood acute lymphoblastic leukemia(ALL).Methods From January 2018 to December 2019,the blood samples were randomlycollected from 275 hospitalized pediatric ALL patients in Beijing Children's Hospital of Capital Medical University.All patients were treated with HD-MTX.Chemiluminescent microparticle immunoassay(CMIA)was used to determine the MTX blood drug concentration at 45 h after infusion.Genotyping of ABCB1(rs1045642),ABCC4(rs7317112),and SLCO1B1(rs11045879 and rs10841753)were determined using MALDI-TOF MS based on MELPA technology.At the same time,chemotherapy-induced toxicity data including liver dysfunction,gastrointestinal disorder,mucositis,myelosuppression,and myocardial damage were recorded.The relationship of SNP polymorphism of these genes and MTX blood drug concentration with AEs were analyzed.Results All the genotypes analyzed were in Hardy-Weinberg equilibrium(P>0.05).A statistically significant relationship between ABCC4 rs7317112 and SLCO1B1 rs11045879 genotype and 45 h MTX blood drug concentration was found(P<0.05).The ABCC4 rs7317112 AA and AG genotypes and SLCO1B1 rs11045879 TT and TC genotypes may also be potential indicators for the excretion delay of MTX(P<0.05).Conclusions ABCC4 rs7317112 and SLCO1B1 rs11045879 polymorphisms are potential genetic markers for individual MTX doses in the treatment of pediatric ALL patients.