急性淋巴细胞白血病（ALL）是儿童中最常见的恶性疾病，甲氨蝶呤（MTX）是ALL的关键药物。关于高剂量甲氨蝶呤（HD-MTX）毒性与甲基四氢叶酸还原酶（MTHFR）C677T和A1298C基因之间的关系的研究得出了不同的结论。本研究旨在探讨MTHFR C677T和A1298C基因多态性与MTX毒性反应的关系。分析了2017年9月至2021年6月在中国南部接受HD-MTX化疗的271名ALL儿童的MTHFR C677T和A1298C基因型，并根据不良事件公共术语（CTCAE）5.0评估和分析了HD-MTX的毒性。MTHFR C677T和A1298C基因多态性与48小时MTX血浓度无关（P>0.05）。无条件逻辑回归模型分析还显示，肝功能受损（OR=1.656，95% CI:1.179-2.324，P<0.05）和黏膜损伤（OR=1.508，95% CI:1.042-2.183，P<0.05）的风险对于杂合突变（CT）和同型突变（TT）突变型显著高于野生型（CC）。低风险的CT+TT突变基因型儿童患中性粒细胞减少和肝功能损害的风险较野生基因型（CC）儿童增加0.498（OR=0.498，95% CI:0.251-0.989，P<0.05）和6.067倍（OR=6.067，95% CI:1.183-31.102，P<0.05），而高风险的CT+TT基因型儿童患黏膜损伤的风险增加1.906倍（OR=1.906，95% CI:1.033-3.518，P<0.05）。ALL儿童中MTHFR A1298C基因型在肝功能损伤和胃肠道毒性反应的发生率上有所不同，但AC+CC变异类型儿童中没有观察到肝功能受损或者胃肠道反应风险的增加。对ALL儿童进行MTHFR基因型测试并基于基因型结果个性化治疗HD-MTX化疗的发展，将有助于预测、预防和减少不良MTX相关毒性反应的发生。

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children, and methotrexate (MTX) is the key drug for ALL. Studies on the relationship between High-Dose methotrexate (HD-MTX) toxicity and methylenetetrahydrofolate reductase (MTHFR) C677T and A1298C genes have drawn different conclusions. This study aimed to investigate the relationship between the polymorphism of MTHFR C677T and A1298C genes and the toxicity responses of MTX.The MTHFR C677T and A1298C genotypes of 271 children with ALL who received HD-MTX chemotherapy in southern China from September 2017 to June 2021 were analyzed, and the toxicity of HD-MTX was evaluated and analyzed according to Common Terminology Criteria for Adverse Events (CTCAE) 5.0.The MTHFR C677T and A1298C gene polymorphisms were not correlated with the 48-hour MTX blood concentrations (P>0.05). Unconditional logistic regression model analysis also revealed that the risk of liver function impairment [odds ratio (OR) =1.656, 95% confidence interval (CI): 1.179-2.324, P<0.05] and mucosal damage (OR =1.508, 95% CI: 1.042-2.183, P<0.05) were 1.656 and 1.508 times higher for the heterozygous mutant (CT), and homozygous mutant (TT) mutant type than for the wild-type (CC), wild-type, respectively. The risk of neutropenia and liver function impairment were 0.498 (OR =0.498, 95% CI: 0.251-0.989, P<0.05) and 6.067 (OR =6.067, 95% CI: 1.183-31.102, P<0.05) times higher in low-risk children with CT+TT mutant genotypes than in those with CC wild genotypes, respectively. Furthermore, the risk of mucosal damage was 1.906 times higher in high-risk children with the CT+TT genotype than in those with the CC genotype (OR =1.906, 95% CI: 1.033-3.518, P<0.05). The MTHFR A1298C genotypes differed in the incidence of liver function damage and gastrointestinal toxic reactions in children with ALL. Nonetheless, no increased risk of liver function impairment nor gastrointestinal reactions in children with the heterozygous mutant (AC)+CC mutation was observed.Advancements in MTHFR genotype testing in children with ALL and the introduction of personalised treatments based on genotype results during HD-MTX chemotherapy will help to predict, prevent, and reduce the occurrence of adverse MTX-related toxic reactions.2023 Translational Pediatrics. All rights reserved.