CAJ | 학술논문

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。
목적：탐토 MTHFR、TS기인다태성연합작용대ALL환인HD-MTX화료후불량반응적영향，이급여MTX혈약농도변화지간적관계；분석MTHFR、TS기인다태성연합작용재개체화치료급질병방치중적작용。방법 ALL환인73례，제취기기인조DNA，PCR확증후측서감정MTHFR C677T、MTHFR A1298C、TS 5’-UTR적기인형。관찰소유ALL환인HD-MTX화료후적독부작용，병감측MTX혈약농도。이Logistic 회귀분석기인다태성여화료독부작용적위험도；채용Fisher정학개솔법비교 HD-MTX 화료후 MTHFR C677T、MTHFR A1298C、TS 적불동기인형지간42～48 h MTX혈약농도적차이，이P＜0.05위차이유현저성。결과（1）MTHFR677 CT／TT합병1298 AC／CC기인형자，기혈홍단백강저발생적풍험하강료2.9배，이점막손해발생적풍험칙증가료4.3배，단차이균무현저성。（2）MTHFR1298 AC／CC합병TS 3R／3R기인형자，기발생점막손해적풍험증가료5.4배，차이유현저성（χ2＝4.911，P＝0.027）。（3）MTHFR677 CT／TT합병TS 3 R／3R기인형여HD-MTX화료독부작용적발생무관。（4）MTHFR677 CT／TT＋MTHFR1298 AC／CC＋TS 3 R／3 R기인형자，기점막손해발생적풍험증가료7.5배，차차이유현저성（χ2＝5.295，P ＝0.021）。결론 TS화MTHFRC677T기인다태성가여ALL환인HD-MTX화료후점막손해적발생유관。
Objective TodiscusstheinfluenceofMTHFRandTSgeneticpolymorphismswith 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 Atotalof73childrenwithacutelymphoblasticleukemiawereselected,andDNAwas 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 1 3.0 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 1 298 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 MTHFR1 298 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/TT,1 298 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 TSandMTHFRC677Tgeneticpolymorphismscanincreasetheinfluenceofthe incidence rate of mucous membrane damage to ALL with MTHFR A1 298C.