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

  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。 

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

  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.