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

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。

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=I. 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.