β-氧化代谢基因多态性与癫痫患儿丙戊酸肝毒性的相关性

Correlation between β-Oxidative Metabolism Gene Polymorphism and Valproic Acid Hepatotoxicity in Children with Epilepsy

目的:分析ACSM2A、CPT1A基因多态性与癫痫患儿丙戊酸(VPA)血药浓度及肝毒性之间的相关性。方法:采用聚合酶链式反应(PCR)和直接测序法检测110例服用丙戊酸单药治疗癫痫患儿外周血ACSM2A rs1133607、CPT1A rs597316基因多态性,并采用液相色谱-质谱联用技术(LC-MS)测定血清VPA稳态谷浓度,记录肝功能等检验指标,比较不同基因型VPA标准血药浓度与肝功能指标的差异。结果:ACSM2A rs1133607突变与丙氨酸氨基转移酶(ALT)、天冬氨酸氨基转移酶(AST)显著相关(P<0.05),ACSM2A rs1133607 CC野生型患儿ALT、AST水平明显高于CT、TT型;CPT1A rs597316 CG突变杂合子与GG突变纯合子VPA标准血药浓度比较差异有统计学意义,GG型患儿VPA标准浓度显著高于CG型患儿(P<0.01)。rs597316位点中突变型GG比野生型CG、CC血清中ALT、AST水平更高,差异有统计学意义(P<0.05)。结论:ACSM2A rs1133607与CPT1A rs597316基因多态性对癫痫患儿服用VPA引起的肝毒性具有预警作用,可为临床合理用药提供参考。

Objective: To analyse the correlation between ACSM2 A, CPT1 A gene polymorphism and valproic acid(VPA) concentration and its related hepatotoxicity in children with epilepsy. Methods: Polymerase chain reaction(PCR) and direct sequencing were used to detect the ACSM2 A rs1133607, CPT1 A rs597316 gene polymorphism in peripheral blood of 110 children with epilepsy treated with VPA, and the liquid chromatography-mass spectrometry(LC-MS) method was used to determine the stable trough concentration of VPA. The liver function and other test indicators were recorded. VPA standard blood drug concentration and liver function indicators of different genotypes were compared. Results: ACSM2 A rs1133607 mutations were significantly associated with alanine aminotransferase(ALT) and aspartate aminotransferase(AST)(P<0.05). The levels of ALT, AST of ACSM2 A rs1133607 CC wild type in children were significantly higher than that of CT and TT types. There was statistically significant difference in VPA standard blood concentration between CPT1 A rs597316 CG mutation heterozygotes and GG mutation homozygotes, and the VPA standard concentration of GG in children was significantly higher than that of CG(P<0.01). The levels of ALT and AST in serum of mutant GG at rs597316 were higher than those of wild type CG and CC, and the difference was statistically significant(P<0.05). Conclusion: The gene polymorphisms of ACSM2 A rs1133607 and CPT1 A rs597316 can provide early warning of hepatotoxicity induced by VPA in children with epilepsy, and provide reference for clinical rational drug use.