妊娠期服用丙戊酸（VPA）会增加女性癫痫患者胎儿畸形风险，研究发现VPA致畸存在易感性，但易感基因及机制至今不详。一碳单位代谢（OCM）基因多态性可影响DNA甲基化过程，而DNA甲基化水平降低被发现与先天性畸形发生相关。我们研究显示，VPA干扰OCM引起DNA甲基化水平下降，但药物-基因相互作用是否会加大对DNA甲基化的影响，增加畸形风险尚不清楚。在预实验中，我们发现OCM关键酶之一亚甲基四氢叶酸还原酶C677T位点可影响VPA单药治疗癫痫患者体内OCM。我们推测OCM基因多态位点影响VPA治疗患者DNA甲基化水平，OCM基因多态位点可能是VPA致畸的易感性来源。本项目将基于DNA甲基化，从基因敲除动物模型和临床病例两个层面，应用化学发光免疫技术、反向液相色谱技术、Sequenom MassARRAY质谱分析技术，证明我们的假说。此研究将为育龄期女性癫痫患者合理使用VPA提供理论指导。

For some women with epilepsy, taking valproate during pregnancy will increase the risk of congenital malformations. Researches indicate that the teratogenic effect of valproate has genetic susceptibility, but till now the susceptibility mechanism is still unknown. DNA hypomethylation has been found to be associated with congenital malformations, while the progress of DNA methylation is mediated by one-carbon metabolism related gene polymorphisms.It has been observed in our research that the effects of valproate monotherapy on one-carbon metabolism may induce specific regions of DNA hypomethylation, but whether the gene-drug interation will exacerbate the effect on DNA methylation and increase the risk of congenital malformations is still unknown. In our preliminary study, the MTHFR C677T which is a key enzyme in one-carbon metabolism influenced the one-carbon metabolism in valproate-treated patients with epilepsy. We hypothesize that one-carbon metabolism related gene polymorphisms affect gene-specific DNA methylation in valproate-treated patients with epilepsy, and it may be the predisposing factor of valproate related malformation. We will verify our scientific hypotheses at the gene knock-out animals and clinical patients levels using chemiluminescent immunoassay, high-performance liquid chromatographic technique and Sequenom MassARRAY platform. Our research will provide reasonable suggestion for women with epilepsy of child-bearing age when they select valproate treatment.