Germline Genetic Variation in an Organic Anion Transporter Polypeptide Associated With Methotrexate Pharmacokinetics and Clinical Effects
Germline Genetic Variation in an Organic Anion Transporter Polypeptide Associated With Methotrexate Pharmacokinetics and Clinical Effects
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DOI：
10.1200/jco.2008.20.4156
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发表时间：
2009-12-10
影响因子：
45.3
通讯作者：
Relling, Mary V.
中科院分区：
文献类型：
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作者：
Trevin, Lisa R.;Shimasaki, Noriko;Relling, Mary V.
目的甲氨蝶呤血药浓度与临床疗效相关。我们的目的是确定新诊断的急性淋巴细胞白血病（ALL）儿童中甲氨蝶呤药代动力学个体间变异的遗传基础。患者和方法我们对500，568个种系单核苷酸多态性（SNP）进行了全基因组分析，以确定遗传如何影响434名ALL儿童中甲氨蝶呤血浆分布，甲氨蝶呤在2至5克/米（2）014个疗程。SNPs进行了验证，在一个独立的队列的206 patients.ResultsAdjusting年龄，种族，性别和甲氨蝶呤方案，最显着的协会与SNPs的有机阴离子转运蛋白多肽，SLCO 1B 1。SLCO 1B 1中的两个SNPs rs 11045879（P = 1.7 x 10（-10））和rs 4149081（P = 1.7 x 10（-9））彼此处于连锁不平衡（LD）（r（2）= 1），并且在SLCO 1B 1中具有功能性多态性T521 C（rs 4149056; r（2）> 0.84）。rs 11045879和rs 4149081在206例患者的独立队列中得到验证（P = 0.018和P = 0.017），其他SLCO 1B 1 SNP也存在于不同的LD区块中。SLCO 1B 1中的SNPs也与GI毒性相关（比值比，15.3至16.4; P = .03至.004）。ConclusionA全基因组询问确定了一个合理的遗传变异，但迄今为止低优先级的候选基因，SLCO 1B 1，作为甲氨蝶呤的药代动力学和临床效果的重要决定因素。
PurposeMethotrexate 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).Patients and MethodsWe 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.ResultsAdjusting 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).ConclusionA 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.