MTHFR基因多态性对骨肉瘤患者首次应用大剂量甲氨蝶呤后不良反应的影响

Effects of MTHFR gene polymorphism on the adverse reactions in osteosarcoma patients after the first high-dose methotrexate treatment

目的探讨MTHFR基因多态性对骨肉瘤患者首次应用大剂量甲氨蝶呤(HD-MTX)后不良反应的影响。方法采用前瞻性研究方法。选择东部战区总医院53例首次入院进行HD-MTX治疗的骨肉瘤患者,根据其人口学因素及MTHFR基因中rs1801133位点的基因多态性确定HD-MTX给药剂量并进行全程化药学监护,收集第1个化疗周期后该药的肝、肾、血液毒性和胃肠道反应数据。采用单因素分析和二元Logistic回归分析对MTX给药剂量、24 h血药浓度、rs1801133位点基因型与上述4种不良反应之间的相关性进行分析。结果CC野生型患者的MTX给药剂量显著高于TT突变型患者(7.97 g/m2 vs.6.98 g/m2,P=0.030),但这种差异不影响MTX的0 h和24 h血药浓度。上述4种不良反应与MTX的给药剂量无相关性。二元Logistic回归分析结果显示,每携带一个T等位基因,患者发生血液学毒性的风险会升高4.13倍(95%置信区间为1.35~12.62,P=0.013)。当MTX 24 h血药浓度阈值设定为2.65μmol/L时,肝功能损害预测的灵敏度为53.33%,特异性为86.96%;当该阈值设定为7.28μmol/L时,肾功能损害预测的灵敏度为100%,特异性为81.63%。结论MTHFR基因中rs1801133位点的基因多态性与MTX的血液学毒性相关;首次应用HD-MTX并且携带T等位基因的患者,其血液学毒性风险较高。MTX 24 h血药浓度与该药的肝、肾毒性相关,监测患者的MTX 24 h血药浓度可以预测肝、肾毒性并及早采取干预措施。

OBJECTIVE To explore the effects of 5,10-methylenetetetrahydrofolate reductase(MTHFR)gene polymorphism on the adverse reactions in patients with osteosarcoma after the first high-dose methotrexate(HD-MTX)treatment.METHODS A prospective study was conducted to include 53 patients with osteosarcoma treated with HD-MTX at the first admission in General Hospital of Eastern Theater Command.The dose of MTX was evaluated according to the polymorphism of rs1801133 in the METHFR gene and demographic factors,then whole pharmaceutical monitoring was conducted.The data on liver toxicity,renal toxicity,hematological toxicity,and gastrointestinal reaction were collected after the first chemotherapy cycle.Single factor analysis and binary Logistic regression analysis were used to analyze the correlation between MTX dose,24 h blood drug concentration,and rs1801133 locus genotype with four adverse reactions.RESULTS The MTX dosage in patients with CC wild type was significantly higher than that in TT mutant type(7.97 g/m2 vs.6.98 g/m2,P=0.030),but this difference did not affect the 0 h and 24 h blood drug concentrations of MTX.The above four adverse reactions were not related to the dose of MTX.The results of binary Logistic regression analysis showed that carrying one T allele increased the risk of developing hematological toxicity by 4.13 times(95%confidence interval:1.35-12.62,P=0.013).When 24 h plasma concentration threshold of MTX was set to 2.65μmol/L,the sensitivity and specificity of predicting liver function damage were 53.33%and 86.96%,respectively;when the threshold was set to 7.28μmol/L,the sensitivity and specificity of predicting renal damage were 100%and 81.63%.CONCLUSIONS The polymorphism of the rs1801133 in the MTHFR gene is associated with hematological toxicity of MTX.Patients who take HD-MTX for the first time and carry the T allele have a high risk of hematological toxicity.The 24 h plasma concentration of MTX is related to liver toxicity and renal toxicity.In addition,monitoring the 24 h blood drug concentration can predict liver and renal toxicity,and take early intervention measures.