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Associations of novel genetic variations in the folate‐related and ARID 5 B genes with the pharmacokinetics and toxicity of high‐dose methotrexate in paediatric acute lymphoblastic leukaemia
Author(s) -
Csordas Katalin,
LautnerCsorba Orsolya,
Semsei Agnes F.,
Harnos Andrea,
Hegyi Marta,
Erdelyi Daniel J.,
Eipel Oliver T.,
Szalai Csaba,
Kovacs Gabor T.
Publication year - 2014
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.12886
Subject(s) - pharmacokinetics , methotrexate , pharmacology , toxicity , single nucleotide polymorphism , snp , slco1b1 , medicine , antifolate , antimetabolite , biology , gene , genotype , genetics
Summary High‐dose methotrexate ( HD ‐ MTX ) plays an important role in the consolidation therapy of acute lymphoblastic leukaemia ( ALL ) in many treatment regimens worldwide. However, there is a large interpatient variability in the pharmacokinetics and toxicity of the drug. We investigated the influence of single nucleotide polymorphisms ( SNP s) in genes of the folate metabolic pathway, transporter molecules and transcription proteins on the pharmacokinetics and toxicity of MTX and 7‐hydroxy‐methotrexate (7‐ OH ‐ MTX ). 63 SNP s of 14 genes were genotyped and a total of 463 HD ‐ MTX courses (administered according to the ALL ‐ BFM 95 and ALL IC ‐ BFM 2002 protocols) were analysed. Haematological, hepatic and renal toxicities, estimated by routine laboratory parameters were evaluated. Random forest and regression trees were used for variable selection and model building. Linear mixed models were established to prove the significance of the selected variables. SNP s (rs4948502, rs4948496, rs4948487) of the ARID 5 B gene were associated with the serum levels of MTX ( P < 0·02), serum levels and area under the curve of 7‐ OH ‐ MTX ( P < 0·02) and with hypoproteinaemia ( P = 0·004). SLCO 1B1 rs4149056 also showed a significant association with serum MTX levels ( P < 0·001). Our findings confirm the association of novel genetic variations in folate‐related and ARID 5B genes with the serum MTX levels and acute toxicity.