摘要目的 探讨三磷酸腺苷结合盒转运体B1(ABCB1)、三磷酸腺苷结合盒转运体C2(ABCC2)和溶质转运蛋白1B1(SLCO1B1)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(MTX)化疗毒性作用的相关性.方法 病例对照研究.收集2005年9月至2011年12月南京医科大学附属南京儿童医院142例ALL患儿外周血,采用均相酶放大免疫分析法(EMIT)测定MTX血药浓度,采用聚合酶链反应-连接酶检测(PCR-LDR)技术对ABCB1 、ABCC2和SLCO1B1基因单核苷酸多态性(SNPs)进行基因分型.结果 MTX存在排泄延迟时,其毒性作用发生风险显著增加(OR =2.828,95％ CI:1.217～6.571,P ＜0.05),SLCO1 B1基因rs4149081和rs11045879位点存在强连锁不平衡(R2 =0.979,P＜0.05).多因素分析显示,SLCO1 B1基因rs4149081AA或rs11045879 CC基因型患儿MTX化疗后易出现排泄延迟(OR =4.41,95％CI:1.537 ～ 12.654,P＝0.042),且发生MTX毒性作用的风险显著高于其他基因型患儿(OR =4.118,95％CI:1.135 ～ 14.944,P＝0.022).未发现其他SNPs与MTX排泄延迟或毒性作用的相关性.结论 SLCO1B1基因rs4149081 AA或rs11045879 CC基因型可能是MTX毒性作用的危险因素.

abstractsObjective To investigate the association between single nucleotide polymorphisms (SNPs) of ATP-binding cassette B1 (ABCB1),ATP-binding cassette C2 (ABCC2) and solute carrier organic anion transporter 1B1 (SLCO1 B1) genes with high dose methotrexate (HDMTX)-induced toxicity in children with acute lymphoblastic leukemia (ALL).Methods This study was designed as a casecontrol.From September of 2005 to December of 2011,the blood samples were randomly collected from 142ALL patients from Nanjing Children's Hospital,Enzyme-multiplied immunoassay technique (EMIT) was used to measure the plasma concentration of MTX,Seven SNPs in ABCB1 (rs1045642,rs2032582,rs1128503),ABCC2 (rs717620,rs2273697) and SLCO1 B1 (rs4149081,rs11045879) genes were detected by polymerase chain reaction-ligase detection reaction (PCR-LDR).Results A significantly increased risk of MTX-induced toxicity was observed in patients with MTX elimination delay (OR ＝ 2.828,95％ CI:1.217-6.571,P ＜ 0.05).Two SNPs in SLCO1B1,rs4149081 and rs11045879 were linkage disequilibrium (LD) with each other (R2 =0.979,P ＜ 0.05).Multivariate analysis revealed that individuals with SLCO1B1 rs4149081 AA genotype or SLCO1B1 rs11045879 CC genotype showed increased incidence of MTX elimination delay (OR =4.41,95％ CI:1.537-12.654,P =0.042),and the two genotypes were also associated with significantly increased risk of MTX-induced toxicity (OR =4.118,95％ CI:1.135-14.944,P =0.022).No association of MTX elimination delay or MTX-induced toxicity with the other SNPs analyzed was found.Conclusions SLCO1B1 rs4149081 AA or SLCO1B1 rs11045879 CC genotypes might be a risk factor for the susceptibility to MTX-induced toxicity in children with ALL.