ABCB1和ABCC2及SLC01B1基因多态性与大剂量甲氨蝶呤化疗毒性作用的相关性

Association of ABCB1, ABCC2 and SLCO1B1 gene polymorphisms with toxicity response of highdose methotrexate chemotherapy

目的探讨三磷酸腺苷结合盒转运体B1（ABCBl）、三磷酸腺苷结合盒转运体c2（ABCC2）和溶质转运蛋白181（SLC0181）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SLC0181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），SLC0181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，SLC0181基因rs4149081AA或rs11045879CC基因型患儿MTX化疗后易m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SLC0181基因rs4149081AA或rs11045879CC基因型可能是MTX毒性作用的危险因素。

Objective 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 1 B1 （SLCO1 B1 ） genes with high dose methotrexate （HDMTX）-induced toxicity in children with acute lymphoblastic leukemia （ALL）. Methods This study was designed as a case- control. From September of 2005 to December of 2011, the blood samples were randomly collected from 142 ALL 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 reaetion-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-iuduced 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.