Treviño Lisa R, Shimasaki Noriko, Yang Wenjian, Panetta John C, Cheng Cheng, Pei Deqing, Chan Diana, Sparreboom Alex, Giacomini Kathleen M, Pui Ching-Hon, Evans William E, Relling Mary V
St Jude Children's Research Hospital, Memphis, TN 38105-2794, USA.
J Clin Oncol. 2009 Dec 10;27(35):5972-8. doi: 10.1200/JCO.2008.20.4156. Epub 2009 Nov 9.
Methotrexate plasma concentration is related to its clinical effects. Our aim was to identify the genetic basis of interindividual variability in methotrexate pharmacokinetics in children with newly diagnosed acute lymphoblastic leukemia (ALL).
We performed a genome-wide analysis of 500,568 germline single-nucleotide polymorphisms (SNPs) to identify how inheritance affects methotrexate plasma disposition among 434 children with ALL who received 3,014 courses of methotrexate at 2 to 5 g/m(2). SNPs were validated in an independent cohort of 206 patients.
Adjusting for age, race, sex, and methotrexate regimen, the most significant associations were with SNPs in the organic anion transporter polypeptide, SLCO1B1. Two SNPs in SLCO1B1, rs11045879 (P = 1.7 x 10(-10)) and rs4149081 (P = 1.7 x 10(-9)), were in linkage disequilibrium (LD) with each other (r(2) = 1) and with a functional polymorphism in SLCO1B1, T521C (rs4149056; r(2) > 0.84). rs11045879 and rs4149081 were validated in an independent cohort of 206 patients (P = .018 and P = .017), as were other SLCO1B1 SNPs residing in different LD blocks. SNPs in SLCO1B1 were also associated with GI toxicity (odds ratio, 15.3 to 16.4; P = .03 to .004).
A genome-wide interrogation identified inherited variations in a plausible, yet heretofore low-priority candidate gene, SLCO1B1, as important determinants of methotrexate's pharmacokinetics and clinical effects.
甲氨蝶呤血药浓度与其临床疗效相关。我们的目的是确定新诊断的急性淋巴细胞白血病（ALL）患儿甲氨蝶呤药代动力学个体间差异的遗传基础。
我们对500,568个种系单核苷酸多态性（SNP）进行了全基因组分析，以确定遗传因素如何影响434例接受2至5 g/m²甲氨蝶呤治疗3014疗程的ALL患儿中甲氨蝶呤的血药浓度。在206例独立队列患者中对SNP进行了验证。
校正年龄、种族、性别和甲氨蝶呤治疗方案后，最显著的关联与有机阴离子转运多肽SLCO1B1中的SNP有关。SLCO1B1中的两个SNP，rs11045879（P = 1.7×10⁻¹⁰）和rs4149081（P = 1.7×10⁻⁹），彼此处于连锁不平衡（LD）状态（r² = 1），并且与SLCO1B1中的一个功能性多态性T521C（rs4149056；r² > 0.84）处于LD状态。rs11045879和rs4149081在206例独立队列患者中得到验证（P = 0.018和P = 0.0
