Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia
Role of polymorphisms in MTHFR and MTHFD1 genes in the outcome of childhood acute lymphoblastic leukemia
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DOI：
10.1038/sj.tpj.6500224
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发表时间：
2004-01-01
影响因子：
2.8
通讯作者：
Moghrabi, A
中科院分区：
文献类型：
--
作者：
Krajinovic, M;Lemieux-Blanchard, É;Moghrabi, A
5，10-亚甲基四氢叶酸还原酶(MTHFR)和亚甲基四氢叶酸脱氢酶(MTHFD1)在叶酸代谢中的中心作用导致了这些酶编码基因的多态性，这些基因可能是抗叶酸化疗药物治疗反应的调节器。201例接受甲氨蝶呤治疗的儿童急性淋巴细胞白血病(ALL)患者的单因素分析显示，MTHFR T677A1298单倍型和MTHFD1 A1958变异的儿童无事件生存(EFS)概率较低(风险比(HR)分别为2.2，95%可信区间(CI)1.0~4.7和2.8，95%CI，1.1~7.3)。多变量分析仅支持MTHFR变异的作用(HR=2.2，95%CI，0.9-5.6)。然而，这两个基因与所有结果的关联似乎在存在属于同一药物作用途径的另一个易发事件的变种时更为明显。MTHFR T677A1298单倍型或MTHFD1 A1958等位基因与胸苷酸合酶(TS)三重重复与TS水平升高相结合，导致EFS显著降低(多变量HR分别为9.0，95%CI，1.9~42.8和8.9，95%CI，1.8~44.6)。这些结果揭示了基因-基因相互作用在叶酸途径中的作用，以及它们如何与所有患者的复发概率相关。
The central role of 5,10-methylenetetrahydrofolate reductase ( MTHFR) and methylenetetrahydrofolate dehydrogenase ( MTHFD1) in folate metabolism renders polymorphisms in genes encoding these enzymes potential modulators of therapeutic response to antifolate chemotherapeutics. The analysis of 201 children treated with methotrexate for childhood acute lymphoblastic leukemia ( ALL) showed that patients with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 variant had a lower probability of event-free survival (EFS) in univariate analysis ( hazard ratio (HR) = 2.2, 95% confidence interval (CI), 1.0 - 4.7 and 2.8, 95% CI, 1.1 - 7.3, respectively). Multivariate analysis supported only the role of the MTHFR variant ( HR = 2.2, 95% CI, 0.9 - 5.6). However, the association of both genes with ALL outcome appears to be more obvious in the presence of another event-predisposing variant belonging to the same path of drug action. The combined effect of a thymidylate synthase (TS) triple repeat associated with increased TS levels, with either the MTHFR T677A1298 haplotype or MTHFD1 A1958 allele, resulted in a highly significant reduction of EFS (multivariate HR = 9.0, 95% CI, 1.9 - 42.8 and 8.9, 95% CI, 1.8 - 44.6, respectively). These results reveal the role of gene - gene interactions within a folate pathway, and how they can correlate with relapse probabilities in ALL patients.