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目的探讨MTHFR、TS基因多态性联合作用对ALL患儿HD-MTX化疗后不良反应的影响,以及与MTX血药浓度变化之间的关系;分析MTHFR、TS基因多态性联合作用在个体化治疗及疾病防治中的作用。方法 ALL患儿73例,提取其基因组DNA,PCR扩增后测序鉴定MTHFR C677T、MTHFR A1298C、TS 5’-UTR的基因型。观察所有ALL患儿HD-MTX化疗后的毒副作用,并监测MTX血药浓度。以Logistic回归分析基因多态性与化疗毒副作用的危险度;采用Fisher精确概率法比较HD-MTX化疗后MTHFR C677T、MTHFR A1298C、TS的不同基因型之间42~48 h MTX血药浓度的差异,以P<0.05为差异有显著性。结果 (1)MTHFR677 CT/TT合并1298 AC/CC基因型者,其血红蛋白降低发生的风险下降了2.9倍,而黏膜损害发生的风险则增加了4.3倍,但差异均无显著性。(2)MTHFR1298 AC/CC合并TS 3R/3R基因型者,其发生黏膜损害的风险增加了5.4倍,差异有显著性(χ2=4.911,P=0.027)。(3)MTHFR677 CT/TT合并TS 3R/3R基因型与HD-MTX化疗毒副作用的发生无关。(4)MTHFR677 CT/TT+MTHFR1298 AC/CC+TS 3R/3R基因型者,其黏膜损害发生的风险增加了7.5倍,且差异有显著性(χ2=5.295,P=0.021)。结论 TS和MTHFR C677T基因多态性可与ALL患儿HD-MTX化疗后黏膜损害的发生有关。
Objective To investigate the effect of combined use of MTHFR and TS gene polymorphisms on the adverse reactions of HD-MTX chemotherapy in children with ALL and the relationship between the changes of MTX and plasma concentrations of MTX. To analyze the association between MTHFR and TS gene polymorphism in individualized The role of treatment and disease prevention and treatment. Methods 73 cases of children with ALL were genomic DNA extracted, PCR-amplified and sequenced to identify MTHFR C677T, MTHFR A1298C, TS 5’-UTR genotype. The toxicities and side effects of HD-MTX chemotherapy were observed in all children with ALL and the MTX plasma concentration was monitored. Logistic regression analysis was used to analyze the risk of gene polymorphism and chemotherapy toxicity. Fisher exact test was used to compare the differences of MTX plasma concentrations between 42-48 h after MTHFR C677T, MTHFR A1298C and TS genotypes after HD-MTX chemotherapy , P <0.05 for the difference was significant. Results (1) MTHFR677 CT / TT genotype 1298 AC / CC had a 2.9-fold decrease in the risk of hemoglobin and a 4.3-fold increase in the risk of mucosal damage, but the difference was insignificant. (2) MTHFR1298 AC / CC combined TS 3R / 3R genotype increased the risk of mucosal injury by 5.4 times, the difference was significant (χ2 = 4.911, P = 0.027). (3) MTHFR677 CT / TT combined with TS 3R / 3R genotype has no relation with the toxic side effects of HD-MTX chemotherapy. (4) The MTHFR677 CT / TT + MTHFR1298 AC / CC + TS 3R / 3R genotype increased the risk of mucosal injury by 7.5-fold, with a significant difference (χ2 = 5.295, P = 0.021). Conclusion TS and MTHFR C677T gene polymorphisms may be associated with the development of mucosal lesions after HD-MTX chemotherapy in children with ALL.