Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
Pharmacogenet Genomics. 2013 Feb;23(2):53-61. doi: 10.1097/FPC.0b013e32835c3b24.
Methotrexate (MTX) is an important component of therapy for pediatric acute lymphoblastic leukemia (ALL). Treatment with MTX often causes toxicity, which can necessitate dose reduction or treatment cessation. Interindividual differences in adverse reactions can be due to different factors, including polymorphisms in key genes. Recently, we confirmed the association between SLCO1B1 rs11045879 polymorphism and toxicity previously proposed by Treviño and colleagues. As SLCO1B1 is a transporter involved in MTX elimination, other polymorphisms in genes from this pathway could also have a role in MTX toxicity. The aim of the present study was to analyze in depth the role of polymorphisms in the genes of the MTX transport pathway as putative toxicity predictors in pediatric ALL.
We analyzed 384 single nucleotide polymorphisms in 12 transporter genes (SLCO1B1, SLCO1B3, SLCO1A2, ABCB1, ABCG2, ABCC1, ABCC2, ABCC3, ABCC4, SLC19A1, SLC22A6 and SLC22A8) and their correlation with different toxicity parameters in 151 pediatric ALL patients treated using the LAL/SHOP protocol.
A significant association with MTX plasma levels was found for 21 polymorphisms from seven genes and 15 haplotypes. After correction, rs9516519 in ABCC4, rs3740065 in ABCC2, and haplotype GCGGG in ABCC2 remained significantly associated.
Our results suggest that polymorphisms in ABCC4 and ABCC2 could be novel markers for MTX toxicity in pediatric ALL.
甲氨蝶呤（MTX）是治疗小儿急性淋巴细胞白血病（ALL）的重要组成部分。MTX 的治疗常引起毒性，这可能需要减少剂量或停止治疗。不良反应的个体间差异可能是由于不同的因素，包括关键基因的多态性。最近，我们证实了 SLCO1B1 rs11045879 多态性与 Treviño 等人先前提出的毒性之间的关联。由于 SLCO1B1 是参与 MTX 消除的转运体，该途径中基因的其他多态性也可能在 MTX 毒性中起作用。本研究的目的是深入分析 MTX 转运途径中基因的多态性作为小儿 ALL 潜在毒性预测因子的作用。
我们分析了 12 个转运体基因（SLCO1B1、SLCO1B3、SLCO1A2、ABCB1、ABCG2、ABCC1、ABCC2、ABCC3、ABCC4、SLC19A1、SLC22A6 和 SLC22A8）中的 384 个单核苷酸多态性，以及它们与 151 例采用 LAL/SHOP 方案治疗的小儿 ALL 患者的不同毒性参数的相关性。
在 7 个基因和 15 个单倍型中，有 21 个多态性与 MTX 血浆水平显著相关。经校正后，ABCC4 中的 rs9516519、ABCC2 中的 rs3740065 和 ABCC2 中的单倍型 GCGGG 仍然与 MTX 毒性显著相关。
我们的研究结果表明，ABCC4 和 ABCC2 中的多态性可能是小儿 ALL 中 MTX 毒性的新标志物。
