ABC亚家族G成员2基因多态性与小儿急性淋巴细胞白血病大剂量甲氨蝶呤治疗效果及肾功能损伤的关系

Relationships of ABC subfamily G member 2 gene polymorphism with therapeutic effect of high-dose methotrexate and renal function injury in children with pediatric acute lymphoblastic leukemia

目的探讨ABC亚家族G成员2(ABCG2)基因多态性与小儿急性淋巴细胞白血病(ALL)大剂量甲氨蝶呤(HDMTX)治疗效果及肾功能损伤的关系。方法选取2011年1月—2019年1月167例ALL患儿为研究对象。所有患儿均进行ABCG2(rs2231137、rs2231142)多态性的基因分型。采用多元回归模型分析遗传多态性对HDMTX相关毒性发生以及患儿无事件生存(EFS)的影响。结果通过限制性片段长度多态性聚合酶链反应(PCR-RFLP)确定的基因型分布为:rs2231137位点包括GG野生型87例(52.1%),AG杂合型52例(31.1%),AA纯合型28例(16.8%);rs2231142位点包括CC野生型115例(68.9%),CT杂合型38例(22.8%),TT纯合型14例(8.3%)。rs2231142中(CT+TT)基因型个体发生肾功能损伤的风险较CC野生型提高了14.14倍(OR=14.14,95%CI为1.26-42.37,P=0.032)。rs2231137中(AG+AA)基因型个体的72个月EFS较GG基因型个体更差,rs2231142中(CT+TT)基因型个体的72个月EFS较CC基因型个体更差,但差异无统计学意义(P>0.05)。结论ALL患儿的ABCG2 rs2231142基因多态性与HDMTX化疗毒副反应中肾功能损伤相关,这可能有助于指导和优化ALL患儿的MTX治疗方案。

Objective To investigate the relationships of ABC subfamily G member 2(ABCG2)gene polymorphism with therapeutic effect of high-dose methotrexate(HDMTX)and renal function injury in children with pediatric acute lymphoblastic leukemia(ALL).Methods A total of 167 children with ALL from January 2011 to January 2019 were selected as research objects.All children were genotyped for ABCG2(rs2231137,rs2231142)polymorphism.Multivariate regression model was used to analyze the effects of genetic polymorphism on the occurrence of HDMTX-related toxicity and event-free survival(EFS)of children.Results The genotypes determined by the restriction fragment length polymorphism polymerase chain reaction(PCR-RFLP)method were located in rs2231137 sites including 87 cases with GG wild type(52.1%),52 cases with AG heterozygous type(31.1%),and 28 cases with AA homozygous type(16.8%)and rs2231142 sites including 115 cases with CC wild type(68.9%),38 cases with CT heterozygous type(22.8%),and 14 cases with TT homozygous type(8.3%).The risk of renal function injury in rs2231142 with(CT+TT)genotype was 14.14 times higher than that with CC wild type(OR=14.14,95%CI,1.26 to 42.37,P=0.032).The 72-month EFS of the individuals with(AG+AA)genotypes in rs2231137 was worse than that with the GG genotype,and the 72-month EFS of the rs2231142 with(CT+TT)genotypes was worse than that with the CC genotype,but the differences were not statistically significant(P>0.05).Conclusion ABCG2 rs2231142 gene polymorphism in children with ALL is associated with renal function injury in the toxic and side effects of HDMTX chemotherapy,which may help to guide and optimize MTX treatment in children with ALL.