MTHFR、TS联合作用与ALL患儿HD-MTX化疗毒副作用的关系

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 3 R／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 3 R／3 R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MTHFRC677T基因多态性可与ALL患儿HD-MTX化疗后黏膜损害的发生有关。

Association of MTHFR and TS genetic polymorphisms with HD-MTX-related toxicity in childhood acute lymphoblastic leukemia

Objective To discuss the influence of MTHFR and TS genetic polymorphisms with MTX-related toxicity to acute lymphoblastic leukemia and the association with MTX plasma concentration; Analysis the role of MTHFR and TS genetic polymorphisms in individualized treatment and prevention of ALL. Methods A total of 73 children with acute lymphoblastie leukemia were selected, and DNA was extracted from their peripheral blood. The genotypes of MTHFR and TS 5＇ -UTR were detected by direct DNA sequencing after PCR. The toxicity response of patients received HD- MTX chemotherapy was observed, and MTX plasma concentration was surveyed. SPSS 13.0 were applied for statistical analysis, the Logistic Regression analysis was applied to study the relationship between genetic polymorphisms and the risk of toxicities ; the Fisher＇ s extended exact test was applied to study the association of MTHFR, TS genetic polymorphisms with 42-48 MTX plasma concentration, P 〈 0.05 were accepted as statistically significant. Results （1）Patients carrying MTHFR677 CT/TT and 1298 AC/CC genotype had 2.9-fold higher incidence rate of anemia and 4.3-fold higher incidence rate of mucous membrane damage, but it had no significant difference. （2） The incidence rate of mucous membrane damage was 5.4-fold higher in carriers of MTHFR1298 AC/CC genotype and TS 3R/3R genotype （ OR = 5.41, CI： 1.22 - 24.09）. （3） MTHFR677 CT/TT and TS 3 R/3 R genotypes had no significant association with the incidence rate of HD-MTX-related toxicities to ALL. （4）Patients carrying MTHFR677 CT/TI＇, 1298 AC/CC and TS 3R/ 3R genotype had 7.5-fold higher incidence rate of mucous membrane damage （OR =7.50,CI： 1.35 41.72）. Conclusions TS and MTHFR C677T genetic polymorphisms can increase the influence of the incidence rate of mucous membrane damage to ALL with MTHFR A1298C.