Association of genetic polymorphisms with hepatotoxicity in patients with childhood acute lymphoblastic leukemia or lymphoma.
The objective of this study was to identify novel pharmacogenetic determinants of treatment-related hepatotoxicity during the maintenance phase in children with acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LBL). Although the authors first determined whether genotypes of drug-metabolizing enzymes and transporters--glutathione S-transferase (GST) genes, GSTM1 positive/null, GSTT1 positive/null and GSTP1 A313G, methylenetetrahydrofolate reductase (MTHFR) C677T, reduced folate carrier 1 (RFC1) G80A, and breast cancer resistant protein (BCRP) C421A--were associated with hepatotoxicity for 24 patients, no significant difference was detected for genotype and allelic frequencies between the patients with and those without severe treatment-related hepatotoxicity. Therefore, the authors explored potential candidate polymorphisms associated with hepatotoxicity using the Illumina Infinium HumanHap300, encompassing more than 318,000 tag single-nucleotide polymorphisms (SNPs), for 8 of 24 patients with or without severe hepatotoxicity. Genome-wide genotyping uncovered a total of 28 candidate SNPs. rs1966862, in Rho GTPase-activating protein 24 (ARHGAP24), was the most significant of the candidates, and the genotypes of rs13424027 (PARD3B), rs1156304 (KCNIP4), rs10255262 (SLC13A1), rs7403531 (RASGRP1), and rs381423 (unidentified gene) were also significantly associated with severe hepatotoxicity. This study suggested rs1966862 (ARHGAP24) and the other SNPs to be predictive factors for drug-induced hepatotoxicity during the maintenance phase in pediatric patients with ALL or LBL.
Horinouchi
Masanori
M
Division of Pharmaceutics, Department of Pharmaceutical Health Care, Faculty of Pharmaceutical Sciences, Himeji Dokkyo University, Himeji, Japan.
Yagi
Mariko
M
Imanishi
Hiroyuki
H
Mori
Takeshi
T
Yanai
Tomoko
T
Hayakawa
Akira
A
Takeshima
Yasuhiro
Y
Hijioka
Michiyo
M
Okamura
Noboru
N
Sakaeda
Toshiyuki
T
Matsuo
Masafumi
M
Okumura
Katsuhiko
K
Nakamura
Tsutomu
T
D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000150:complications* / Q000235:genetics; D011237:Predictive Value of Tests
C497033:ARHGAP24 protein, human; D020690:GTPase-Activating Proteins