Analysis of the frequency distribution of five single‐nucleotide polymorphisms of the MTRRgene in a Chinese pediatric population with acute lymphoblastic leukemia

Abstract

Study Objective The objective of the present study was to examine the frequency distribution of five single‐nucleotide polymorphisms (SNPs; rs1801394 A>G, rs1532268 C>T, rs162036 A>G, rs10380 C>T, and rs9332 C>T) of the methionine synthase reductase (MTRR) gene, their effects on methotrexate (MTX) concentration, and the risk of relapse in a Chinese pediatric population with acute lymphoblastic leukemia (ALL). Design This was a retrospective single‐center study, and all analyses were exploratory. Setting Pediatric Department of Beijing Shijitan Hospital, Capital Medical University, Beijing, China. Patients One hundred and forty pediatric patients with ALL. Intervention All patients were treated according to the Chinese Children's Leukemia Group (CCLG)‐ALL 2008 protocol. Measurements and Main Results Serum MTX concentrations were measured using fluorescence polarization immunoassay. Genotyping of five SNPs was performed using the Sequenom MassARRAY iPLEX platform. Chinese children with ALL had a significantly lower frequency of rs1801394 G than European (EUR) and South Asian (SAS) populations; significantly lower frequency of rs1532268 T than American (AMR), EUR, and SAS populations; and significantly lower frequencies of rs162036 G, rs10380 T, and rs9332 T than African and AMR populations (p < 0.01). Seven haplotypes were observed, with the ACACC being the most common haplotype (49.9%) in our study. The median dose‐normalized concentrations of MTX in serum at 24 h in children with rs1532268 CT and TT genotypes were significantly higher than those with CC genotype (p = 0.04). Compared with children with AA‐CC‐AA‐CC‐CC diplotype, a significantly higher risk of relapse was observed in children with AG‐CC‐AA‐CC‐CC and AG‐CC‐AG‐CC‐CC diplotypes (p = 0.03 and 0.003, respectively). Conclusions The present study confirmed the ethnic differences in the distribution of MTRR rs1801394, rs1532268, rs162036, rs10380, and rs9332 polymorphisms. The rs1532268 polymorphism had greater effects on MTX disposition. The AG‐CC‐AA‐CC‐CC and AG‐CC‐AG‐CC‐CC diplotypes were significantly associated with higher risk of relapse of ALL.

Involvement of the ABCB1 C3435T Variant but Not the MTHFR C677T or MTHFR A1298C Variant in High-Dose Methotrexate-Induced Toxicity in Pediatric Acute Lymphoblastic Leukemia Patients in China

“… 29 Response to MTX largely varies among patients receiving HD-MTX treatment. 2 , 30 Research on genetic predictors for MTX-induced toxicities would be helpful for selecting patients who may benefit from personalized treatment strategies. Several SNPs involved in MTX transport and metabolism have been explored as predictors of the efficacy and toxicity of MTX in treatment of children with ALL.…”