Genome-wide study of methotrexate clearance replicates SLCO1B1
Genome-wide study of methotrexate clearance replicates SLCO1B1
复制标题
DOI：
10.1182/blood-2012-08-452839
复制
发表时间：
2013-02-07
期刊：
影响因子：
20.3
通讯作者：
Relling, Mary V.
中科院分区：
文献类型：
--
作者：
Ramsey, Laura B.;Panetta, John C.;Relling, Mary V.
甲氨蝶呤清除率影响急性淋巴细胞白血病（ALL）患儿的治愈和毒性。我们估计了1279例接受甲氨蝶呤治疗的ALL患者(24小时输注1 g/m（2)剂量或4小时输注2 g/m(2)剂量）在儿童肿瘤组P9904和P9905方案中的血浆清除率。年龄较大的儿童（P = 7 × 10(-7)）、女孩（P = 2.7 × 10(-4)）和接受延迟强化期的患者（P = 0.0022）的甲氨蝶呤清除率较低。一项全基因组分析显示，甲氨蝶呤清除与有机阴离子转运基因SLCO1B1多态性相关（P = 2.1 x 10(-11)）。这重复了在St Jude ALL治疗方案中使用不同时间表的高剂量甲氨蝶呤的结果；综合荟萃分析得出甲氨蝶呤清除率与SLCO1B1 SNP rs4149056相关的P值为5.7 x 10（19）。5种不同的甲氨蝶呤治疗方案验证了这种变异，巩固了甲氨蝶呤清除的药物基因组决定因素的稳健性。本研究在http://www.clinicaltrials.gov注册为NCT00005585和NCT00005596。(血。2013;121 (6):898 - 904)
Methotrexate clearance can influence the cure of and toxicity in children with acute lymphoblastic leukemia (ALL). We estimated methotrexate plasma clearance for 1279 patients with ALL treated with methotrexate (24-hour infusion of a 1 g/m(2) dose or 4-hour infusion of a 2 g/m(2) dose) on the Children's Oncology Group P9904 and P9905 protocols. Methotrexate clearance was lower in older children (P = 7 x 10(-7)), girls (P = 2.7 x 10(-4)), and those who received a delayed-intensification phase (P = .0022). A genome-wide analysis showed that methotrexate clearance was associated with polymorphisms in the organic anion transporter gene SLCO1B1 (P = 2.1 x 10(-11)). This replicates findings using different schedules of high-dose methotrexate in St Jude ALL treatment protocols; a combined meta-analysis yields a P value of 5.7 x 10(-19) for the association of methotrexate clearance with SLCO1B1 SNP rs4149056. Validation of this variant with 5 different treatment regimens of methotrexate solidifies the robustness of this pharmacogenomic determinant of methotrexate clearance. This study is registered at http://www.clinicaltrials.gov as NCT00005585 and NCT00005596. (Blood. 2013;121(6):898-904)