Genome-wide study of methotrexate clearance replicates SLCO1B1

Laura B. Ramsey, John C. Panetta, Colton Smith, Wenjian Yang, Yiping Fan, Naomi J. Winick, Paul L. Martin, Cheng Cheng, Meenakshi Devidas, Ching Hon Pui, William E. Evans, Stephen P. Hunger, Mignon Loh, Mary V. Relling

Research output: Contribution to journalArticle

105 Scopus citations

Abstract

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/m2 dose or 4-hour infusion of a 2 g/m2 dose) on the Children's Oncology Group P9904 and P9905 protocols. Methotrexate clearance was lower in older children (P = 7 × 10-7), girls (P = 2.7 × 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 × 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 × 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.

Original languageEnglish (US)
Pages (from-to)898-904
Number of pages7
JournalBlood
Volume121
Issue number6
DOIs
StatePublished - Feb 7 2013

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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    Ramsey, L. B., Panetta, J. C., Smith, C., Yang, W., Fan, Y., Winick, N. J., Martin, P. L., Cheng, C., Devidas, M., Pui, C. H., Evans, W. E., Hunger, S. P., Loh, M., & Relling, M. V. (2013). Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood, 121(6), 898-904. https://doi.org/10.1182/blood-2012-08-452839