title: Genome-wide study of methotrexate clearance replicates SLCO1B1.
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 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.
authors.affiliation: Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, Memphis, TN 38105, USA.
authors.forename: Laura B
authors.initials: LB
authors.lastname: Ramsey
authors.forename: John C
authors.initials: JC
authors.lastname: Panetta
authors.forename: Colton
authors.initials: C
authors.lastname: Smith
authors.forename: Wenjian
authors.initials: W
authors.lastname: Yang
authors.forename: Yiping
authors.initials: Y
authors.lastname: Fan
authors.forename: Naomi J
authors.initials: NJ
authors.lastname: Winick
authors.forename: Paul L
authors.initials: PL
authors.lastname: Martin
authors.forename: Cheng
authors.initials: C
authors.lastname: Cheng
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Devidas
authors.forename: Ching-Hon
authors.initials: CH
authors.lastname: Pui
authors.forename: William E
authors.initials: WE
authors.lastname: Evans
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Hunger
authors.forename: Mignon
authors.initials: M
authors.lastname: Loh
authors.forename: Mary V
authors.initials: MV
authors.lastname: Relling
mesh_terms: D000293:Adolescent; D000483:Alleles; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D004305:Dose-Response Relationship, Drug; D005260:Female; D005787:Gene Frequency; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D007223:Infant; D007262:Infusions, Intravenous; D002955:Leucovorin / Q000008:administration & dosage; D016014:Linear Models; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate / Q000008:administration & dosage / Q000493:pharmacokinetics*; D015999:Multivariate Analysis; D027361:Organic Anion Transporters / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
chemical_list: D027381:Liver-Specific Organic Anion Transporter 1; D027361:Organic Anion Transporters; C503999:SLCO1B1 protein, human; D002955:Leucovorin; D008727:Methotrexate