title: Effect of polymorphisms within methotrexate pathway genes on methotrexate toxicity and plasma levels in adults with hematological malignancies.
abstract: OBJECTIVE
  Pharmacogenetics of methotrexate (MTX) contributes to interindividual differences in toxicity. We aimed to evaluate the impact of SNPs within the MTX pathway genes on MTX-induced toxicity and MTX plasma levels at 48 h following treatment in Asian adults with acute lymphoblastic leukemia or non-Hodgkin lymphoma.
  
  
  METHODS
  Patients (n = 71) were genotyped for MTHFR C677T, MTHFR A1298C, SLC19A1 G80A, ABCG2 C421A and ABCB1 C3435T using the Sequenom MassARRAY platform. Plasma MTX concentrations at 48 h were measured by fluorescence polarization immunoassay.
  
  
  RESULTS
  Forty-eight patients had hematopoietic toxicity, 51 had hepatic toxicity and 36 had mucositis. Patients homozygous for MTHFR 677TT were associated with increased risk of both hematopoietic (odds ratio [OR]: 9.03; 95% CI: 2.28-36.16; p = 0.002) and hepatic (OR: 3.92; 95% CI: 1.01-15.11; p = 0.036) toxicities. Hepatic toxicity was associated with SLC19A1 G80A (OR: 5.27, 95% CI: 1.21-22.72; p = 0.032) and ABCB1 C3435T (OR: 8.62; 95% CI: 1.96-37.57; p = 0.004). However, polymorphisms in MTHFR A1298C and ABCG2 C421A were not associated with any of the toxicities, and mucositis was not associated with any polymorphisms of the MTX pathway genes. Patients with MTHFR C677T and ABCB1 C3435T polymorphisms appear to have significantly higher MTX plasma concentrations (p < 0.05).
  
  
  CONCLUSIONS
  Our results in Asian adults provides evidence for the contribution pharmacogenetics to the toxicity of high-dose MTX and plasma MTX concentrations at 48 h following treatment in patients with acute lymphoblastic leukemia or non-Hodgkin lymphoma. These results will contribute towards the effort of MTX therapy individualization.
authors.affiliation: The Pharmacogenomics Laboratory, Department of Pharmacology, University of Malaya, Kuala Lumpur, Malaysia.
authors.forename: Sujatha
authors.initials: S
authors.lastname: Suthandiram
authors.forename: Gin-Gin
authors.initials: GG
authors.lastname: Gan
authors.forename: Shamsul Mohd
authors.initials: SM
authors.lastname: Zain
authors.forename: Ping-Chong
authors.initials: PC
authors.lastname: Bee
authors.forename: Lay-Hoong
authors.initials: LH
authors.lastname: Lian
authors.forename: Kian-Meng
authors.initials: KM
authors.lastname: Chang
authors.forename: Tee-Chuan
authors.initials: TC
authors.lastname: Ong
authors.forename: Zahurin
authors.initials: Z
authors.lastname: Mohamed
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use*; D044466:Asian People / Q000235:genetics; D005260:Female; D005838:Genotype; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D006801:Humans; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy / Q000235:genetics; D008297:Male; D008727:Methotrexate / Q000009:adverse effects* / Q000097:blood / Q000627:therapeutic use*; D008875:Middle Aged; D010597:Pharmacogenetics / Q000379:methods; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics; D012306:Risk; D055815:Young Adult
chemical_list: D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate
keywords: NHL; SNP; high-dose methotrexate; methotrexate plasma concentration; methotrexate toxicity; non-Hodgkin lymphoma; single nucleotide polymorphism