Influence of genetic polymorphisms of FPGS, GGH, and MTHFR on serum methotrexate levels in Chinese children with acute lymphoblastic leukemia

摘要

Purpose: To investigate the correlation between common genetic polymorphisms of folylpolyglutamate synthase (FPGS), gamma-glutamyl hydrolase (GGH), and methylenetetrahydrofolate reductase (MTHFR) and serum levels of methotrexate (MTX) in Chinese children with acute lymphoblastic leukemia (ALL). Methods: Ninety-one children with ALL who received high-dose MTX were recruited. The polymorphisms FPGS (rs1544105 GA), GGH (rs3758149 CT), and MTHFR (rs1801133 CT) were genotyped through polymerase chain reaction-restriction fragment length polymorphism analysis. Serum MTX was measured by fluorescence polarization immunoassay. The association between targeted polymorphisms and MTX concentration-to-dose (C/D) ratios was assessed, and between targeted polymorphisms and the percent of MTX above the therapeutic threshold (40 μmol/L). Results: The minor allele frequencies of rs1544105 G (34.1 %), rs3758149 T (19.2 %), and rs1801133 C (48.4 %) observed in our population were significantly lower than those reported for European populations (64.2, 30.8, and 69.0 %, respectively). The association between the GGH rs3758149 polymorphism and MTX C/D was gender-specific; in girls, the MTX C/D at 24 h of GGH rs3758149 CC carriers (12.09 μmol/L per g/m2) was significantly lower than that of CT or TT carriers (16.80 μmol/L per g/m 2). The percent of serum MTX above the therapeutic threshold in GGH rs3758149 CC carriers (18.3 %) was significantly lower than that of CT and TT carriers (38.7 %). The MTX C/D ratios at 24 h and the percent of MTX 40 μmol/L for the A-T-T (three variant alleles) haplotype were significantly higher than those for other haplotypes combined (P 0.05). Conclusions: These data indicate that FPGS rs1544105, GGH rs3758149, and MTHFR rs1801133 polymorphisms contribute to the variability of MTX pharmacokinetics, and their genotyping may be useful to reduce toxicities associated with MTX therapy.