癫痫患者OCM相关酶SNPs位点基因型和抗癫痫发作药物对OCM代谢物水平的影响  

Effects of genotypes of one-carbon metabolism(OCM)-related enzyme single nucleotide polymorphisms sites and anti-epileptic drugs on OCM metabolite levels in epileptic patients

作　　者：陈傲寒 黎银潮 朱少芳 赵怡然 林婉蓉 周列民 Chen Aohan;Li Yinchao;Zhu Shaofang;Zhao Yiran;Lin Wanrong;Zhou Liemin(Neuromedicine Center,Seventh Affiliated Hospital,Sun Yat-Sen University,Shenzhen 518107,China)

机构地区：[1]中山大学附属第七医院神经医学中心,深圳518107

出　　处：《中华神经医学杂志》2022年第7期657-663,共7页Chinese Journal of Neuromedicine

基　　金：国家自然科学基金(82071447);深圳市"医疗卫生三名工程"(SZSM201911003)。

摘　　要：目的分析抗癫痫发作药物、一碳单位代谢(OCM)相关酶单核苷酸多态性(SNPs)位点基因型对癫痫患者体内OCM代谢物水平的影响,筛选丙戊酸(VPA)致畸的易感基因。方法选择中山大学附属第一医院神经内科和附属第七医院神经医学中心自2019年1月至2020年12月收治的372例癫痫患者,将服用VPA、左乙拉西坦(LEV)、拉莫三嗪(LTG)、奥卡西平(OXC)超过6个月且规律用药期间无发作的患者分别归为VPA组(95例)、LEV组(61例)、LTG组(57例)、OXC组(70例),将从未服用过抗癫痫发作药物或就诊前6个月未服用抗癫痫发作药物患者归为空白对照组(89例)。采用全自动化学发光免疫法测定各组患者血浆叶酸(FA)、维生素B_(12)(VitB_(12))和同型半胱氨酸(Hcy)水平,采用Sequenom iPLEX法检测患者OCM相关酶SNPs位点的基因型。结果(1)与LEV组、空白对照组比较,VPA组患者的FA水平降低,Hcy水平增高,差异均有统计学意义(P<0.05)。(2)DNA甲基转移酶(DNMT)3a rs12987326(-178G>A)位点GA型患者的Hcy水平较GG型高,DNMT1 rs2288350(82G>C)位点GC型患者的Hcy水平较GG型高,DNMT1 rs75616428(55850G>C)位点GC型患者的VitB_(12)水平较GG型低,差异均有统计学意义(P<0.05)。DNMT1 rs1863771(128G>A)位点GA+AA型患者的FA水平较GG型高,叶酸受体蛋白2(FOLR2)rs2298444(59T>C)位点CT+CC型患者的Hcy水平较TT型高,5,10-亚甲基四氢叶酸还原酶(MTHFR)rs1801131(1298A>C)位点CC+AC型患者的Hcy水平较AA型高,DNMT3a rs6722613(2327C>T)位点CT+TT型患者的VitB_(12)水平较CC型低,差异均有统计学意义(P<0.05)。结论服用VPA的癫痫患者FA水平降低、Hcy水平升高,此外OCM相关酶SNPs位点基因型亦影响癫痫患者体内OCM代谢物水平。建议妊娠期癫痫患者避免使用VPA,或用药前检测SNPs位点基因型,以降低胎儿畸形的发生率。Objective To explore the effects of genotypes of one-carbon metabolism(OCM)-related enzyme single nucleotide polymorphisms(SNPs)sites and anti-epileptic drugs on OCM metabolite levels in epileptic patients,and to screen valproic acid(VPA)teratogenic susceptibility genes.Methods Three hundred and seventy-two epileptic patients,admitted to our hospital from January 2019 to December 2020,were enrolled in the study;patients taking VPA,levetiracetam(LEV),lamotrigine(LTG)or oxcarbazepine(OXC)for more than 6 months without attack during regular medication were classified as VPA group(n=95),LEV group(n=61),LTG group(n=57)and OXC group(n=70);firstly diagnosed epileptic patients who had never taken antiepileptic drugs or had not taken antiepileptic drugs in the previous 6 months were assigned into blank control group(n=89).Plasma folic acid(FA),vitamin B_(12)(VitB_(12))and homocysteine(Hcy)levels were determined by automatic chemiluminescence immunoassay,and genotypes of OCM-related enzyme SNPs sites were detected by Sequenom iPLEX.Results(1)As compared with LEV group and blank control group,VPA group had significantly decreased FA level and significantly increased Hcy level(P<0.05).(2)Patients with DNA methyltransferase(DNMT)3a rs12987326(-178G>A)GA type had significantly higher Hcy level than those with GG type(P<0.05);patients with DNMT1 rs2288350(82G>C)GC type had significantly higher Hcy level than those with GG type(P<0.05);patients with DNMT1 rs75616428(55850G>C)GC type had significantly lower VitB_(12) level than those with GG type(P<0.05).Patients with DNMT1 rs1863771(128G>A)GA+AA type had significantly higher FA level than those with GG type,patients with folate receptor 2 rs2298444(59T>C)CT+CC type had significantly higher Hcy level than those with TT type,patients with 5,10-methylenetetrahydrofolate reductase rs1801131(1298A>C)AC+CC type had significantly higher Hcy level than those with AA type,and patients with DNMT3a rs6722613(2327C>T)CT+TT type had significantly lower VitB_(12) level than those with CC type

关 键 词：癫痫 丙戊酸 同型半胱氨酸 单核苷酸多态性 致畸 

分 类 号：R742.1[医药卫生—神经病学与精神病学]