多药耐药相关蛋白1基因多态性及蛋白表达与癫痫患者耐药机制关系的研究  

Association of polymorphisms and protein expression of the multidrug resistance-associated protein 1 gene with drug resistance in patients with epilepsy

作　　者：贺淑慧 孙洪英[1] HE Shu-Hui;SUN Hong-Ying(Department of Neurology,The First Affiliated Hospital of Baotou Medical College,Baotou,Inner Mongolia 014010,China)

机构地区：[1]包头医学院第一附属医院神经内科,内蒙古包头014010

出　　处：《国际神经病学神经外科学杂志》2020年第2期141-147,共7页Journal of International Neurology and Neurosurgery

基　　金：内蒙古自治区高等学校科学研究项目(NJZY17256)。

摘　　要：目的探讨多药耐药相关蛋白1 (MRP1)基因G128C (rs41395947)、C218T (rs41494447)、G2168A(rs4148356)、G3173A(rs41410450)多态性及MRP1蛋白水平与癫痫耐药的关系,进一步探究MRP1基因多态性更易导致癫痫患者对哪种抗癫痫药物(AED)耐药。方法对2017年11月至2018年6月就诊于包头医学院第一附属医院门诊、病房和包头中心医院癫痫门诊,且诊断符合2014年国际抗癫痫联盟关于癫痫的诊断标准,均经视频脑电图及头颅MRI证实的31例耐药性癫痫患者和67例药物敏感性癫痫患者进行调查问卷。采用DNA测序的方法分别检测MRP1基因,从而分析其多态性分布情况,采用酶联免疫吸附(ELISA)测定的方法分别检测两组人群中MRP1蛋白的浓度,采用化学发光法检测癫痫患者卡马西平、丙戊酸钠的血药浓度。结果经DNA测序发现,AED耐药组和AED敏感组癫痫患者MRP1基因中第128位和第3173位未出现基因突变,第218位、2168位中存在单核苷酸多态性。MRP1的C218 T(rs41494447)突变5例,其中AED耐药组4例,ADE敏感组1例,C218T(rs41494447)多态性在AED耐药组与AED敏感组中的分布差异无统计学意义(P> 0. 05)。MRP1的G2168A(rs4148356)突变9例,其中AED耐药组6例,ADE敏感组3例,G2168 A (rs4148356)多态性在AED耐药组与AED敏感组中的分布差异有统计学意义(P <0. 05);MRP1的2168位GA基因型在AED耐药组67%高于AED敏感组33%。MRP1蛋白水平测定结果:AED耐药组高于AED敏感组,差异有统计学意义(P <0. 05)。MRP1的2168位GA基因型患者的卡马西平、丙戊酸钠血药浓度低于GG基因型患者,差异有统计学意义(P <0. 05)。比较MRP1的C218T(rs41494447)、G2168A(rs4148356)不同基因型的MRP1浓度,差异无统计学意义(P> 0. 05)。结论MRP1的G2168A (rs4148356)多态性可能是癫痫患者发生AEDs耐药的风险位点。MRP1基因的G128 C (rs41395947)、C218 T (rs41494447)、G3173 A (rs41410450)三个位点可能不是癫痫患者发生AEDs耐药的风险位点Objective To investigate the association of the polymorphisms of the multidrug resistance-associated protein 1(MRP1)gene-G128C(rs41395947),C218T(rs41494447),G2168A(rs4148356),and G3173A(rs41410450),and serum MRP1 levels with drug resistance in epilepsy,and to further determine which antiepileptic drug ( AED) epileptic patients with the polymorphismstend to be resistant to. Methods A questionnaire was conducted among epileptic patients ( 31 cases resistant to AEDs and 67 casessensitive to AEDs) who attended the outpatient department and ward of the First Affiliated Hospital of Baotou Medical College or theEpilepsy Clinic of Baotou Central Hospital from November 2017 to June 2018,and got a diagnosis in accordance with the 2014 diagnosticcriteria for epilepsy published by International League Against Epilepsy and confirmed by video electroencephalogram and cranialMRI. DNA sequencing was used to analyze the distribution of MRP1 polymorphisms. Enzyme-linked immunosorbent assay was appliedto measure serum MRP1 concentrations. Chemiluminescence was used to determine blood concentrations of carbamazepine and valproatein the epileptic patients. Results DNA sequencing showed that single nucleotide polymorphism was not found at 128 bp and3173 bp of the MRP1 gene,but present at 218 bp and 2168 bp,in the AEDs-resistant patients and AEDs-sensitive patients. Five patientscarried a C218T ( rs41494447) mutation,with four in the AEDs-resistant group and one in the AEDs-sensitive group,and therewas no significant difference in the distribution of C218T ( rs41494447) polymorphism between the two groups ( P > 0. 05).Nine casesharbored a G2168A ( rs4148356) mutation,with six in the AEDs-resistant group and three in the AEDs-sensitive group,showing a significantdifference in the distribution of G2168A ( rs4148356) polymorphism between the two groups ( P < 0. 05);the proportion of GAgenotype was higher in the AEDs-resistant group ( 67%) than in the AEDs-sensitive group ( 33%).The concentration of MRP1 in theAEDs-resistant group was sign

关 键 词：癫痫 耐药 多药耐药相关蛋白1 基因多态性 抗癫痫药物 

分 类 号：R742.1[医药卫生—神经病学与精神病学]