MTHFR基因多态性与大剂量甲氨蝶呤治疗儿童急性淋巴细胞白血病的临床疗效及药物不良反应的相关性分析

Association of MTHFR gene polymorphism with efficacy and adverse drug reactions of high-dose methotrexate in the treatment of childhood acute lymphoblastic leukemia

目的探讨亚甲基四氢叶酸还原酶(MTHFR)基因多态性与大剂量甲氨蝶呤(MTX)治疗急性淋巴细胞白血病(ALL)患儿的疗效及药物不良反应(ADR)的相关性。方法在60例ALL患儿中,标危患儿给予3 g·m^(-2) MTX,中、高危患儿给予5 g·m^(-2) MTX。于治疗前收集患儿血样,用聚合酶链反应-限制性酶切片段长度多态性技术对MTHFR基因C677T和A1298C多态性进行检测,分析各基因型与患儿治疗后临床疗效及ADR的相关性。结果在60例ALL患儿中,MTHFR基因C677T位点CC,CT和TT型分别占40.00%,45.00%和15.00%,A1298C位点AA,AC和CC型分别占55.00%,35.00%和10.00%。随访期间共8例患儿复发,其复发率为13.33%。MTHFR C677T位点CC,CT和TT型的复发率分别为16.67%,14.81%和0,差异均无统计学意义(均P>0.05);MTHFR C677T位点AA,AC和CC型的复发率分别为12.12%,14.28%和16.67%,差异均无统计学意义(均P>0.05)。未发现MTHFR C677T各基因型与大剂量MTX化疗后在胃肠道反应、骨髓抑制、肝损害以及黏膜损伤等ADR的发生风险相关(均P>0.05)。MTHFR A1298C各基因型与大剂量MTX化疗后的胃肠道反应、黏膜损伤等ADR发生风险相关,差异均有统计学意义(均P<0.05),而与骨髓抑制、肝损害等ADR发生风险无关,差异均无统计学意义(均P>0.05)。结论MTHFR A1298C基因多态性与ALL患儿大剂量MTX化疗后的ADR有关,未发现其与疗效存在相关性;MTHFR C677T基因多态性与ALL患儿大剂量MTX化疗后的ADR和疗效均无相关性。

Objective To investigate the correlation between methylenetetrahydrofolate reductase(MTHFR)gene polymorphism and the efficacy and adverse drug reactions(ADRs)of acute lymphocytic leukemia(ALL)children with high-dose methotrexate(MTX)treatment.Methods A total of 60 children with ALL were given 3 g·m^(-2) MTX for the standard-risk children,and 5 g·m^(-2) MTX for the medium and high-risk children.Before treatment,the blood samples of children were collected.The polymerase chain reaction-restriction enzyme digestion fragment length polymorphism technology was used to detect Chin J Clin Pharmacol 3057 Vol.37 No.22 November 2021(Serial No.348)the M THFR C677T and A1298C polymorphisms.To analyze the correlation between MTHFR C677T and A1298C genotypes and clinical efficacy and ADRs in children after treatment.Results Among 60 children with ALL,the CC,CT and TT genotypes of MTHFR C677T were 40.00%,45.00%and 15.00%,and the AA,AC and CC genotypes of MTHFR A1298C were 55.00%,35.00%and 10.00%,respectively.During the follow-up period,8 cases recurred,and the recurrent rate was 13.33%.The recurrent rates of the CC,CT and TT types at the MTHFR C677T site were 16.67%,14.81%and 0,and the differences were not statistically significant(all P>0.05).The recurrent rates of the AA,AC and CC types at the MTHFR C677T site were 12.12%,14.28%and 16.67%,and the difference was not statistically significant(all P>0.05).The genotypes of MTHFR C677T were not found to be associated with the risk of ADR such as gastrointestinal reactions,bone marrow suppression,liver damage and mucosal damage after high-dose MTX chemotherapy(all P>0.05).Each genotype of MTHFR A1298C were related to the risk of ADR such as gastrointestinal reaction and mucosal damage after high-dose MTX chemotherapy,and the difference was statistically significant(all P<0.05),bu it was not related to the risk of ADR such as bone marrow suppression and liver damage,the difference was not statistically significant(all P>0.05).Conclusion MTHFR A1298C gene polymorphism is associated with ADR in children with ALL after high-dose MTX chemotherapy,but no correlation was found between MTHFR A1298C gene polymorphism and curative effect.And no correlation was found between MTHFR C677T gene polymorphism and ADR and efficacy in children with ALL after high-dose MTX chemotherapy.