胸苷酸合成酶基因多态性与ALL儿童HD-MTX毒副作用的相关性

Correlation between the polymorphism of thymidylate synthase gene and the toxicity of high dose MTX in childhood acute lymphoblastic leukemia

    摘要
  • 摘要:
      目的  研究胸苷酸合成酶(TS)基因(TYMS)多态性与大剂量甲氨蝶呤(HD-MTX)治疗儿童急性淋巴细胞白血病(ALL)时毒副作用的相关性。
      方法  75例ALL中有52例接受了HD-MTX治疗, 对患儿用药后的一般反应、皮肤黏膜损害、骨髓抑制等临床表现和血尿常规、肝肾功能、心肌酶、心电图等进行统计分析, 并采用DNA直接测序技术检测ALL儿童TYMS多态性(rs699517、rs2790和rs11280056), 分析MTX毒副作用与其关系。
      结果  TYMS rs2790与ALL儿童性别相关, 与AA基因型相比, 携带等位基因G者男孩数约是女孩的3倍(OR=3.05, 95%CI=1.14~8.19, P=0.024)。rs2790基因型与HD-MTX引起的中性粒细胞减少发生也相关, GG基因型使中性粒细胞减少的发生危险降低(OR=0.07, 95%CI=0.01~0.64, P=0.026)。rs699517和rs11280056与ALL儿童发病年龄、性别以及HD-MTX毒副作用均无相关性(P > 0.05)。
      结论  TYMS rs2790可能与HD-MTX毒副作用具有相关性, 对ALL男性儿童影响较大。

     

    Abstract:
      Objective  This work aimed to investigate the influence of polymorphisms in thymidylate synthase gene(TYMS) on toxicities related to high dose methotrexate(HD-MTX) in children with acute lymphoblastic leukemia(ALL).
      Methods  Direct sequencing was conducted to confirm the 3'-untranslated region(3'-UTR) polymorphisms(rs699517, rs2790, and rs11280056) in TYMS of 75 ALL children and 83 healthy subjects(controls).Clinical manifestations of 52 ALL children treated with HD-MTX, including general state of health, mucocutaneous damage, myelo-suppression, blood and urine routine examinations, hepatic and renal functions, ECG, myocardial enzymes, and so on, were evaluated retrospectively.Then, the effects of TYMS polymorphisms on toxicities of HD-MTX were investigated.
      Results  Compared with the TYMS rs2790 AA genotype, the number of boys carrying allele G was approximately three times that of girls(OR=3.05, 95% CI=1.14-8.19, P=0.024).TheTYMS rs2790 genotypes were related with the risk of neutropenia.The genotype GG played a protective role that reduced the risk of neutropenia(OR=0.07, 95%CI=0.01-0.64, P=0.026).TYMS rs699517 and rs11280056 were not correlated with toxicities related to HD-MTX(P > 0.05).
      Conclusion  TYMS rs2790 may probably be associated with HD-MTX toxicity in children ALL patients, especially boys.

     

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