發(fā)布時間：2018-03-28 20:18

  本文選題：部分性癲癇　切入點：耐藥　出處：《中南大學》2014年博士論文

【摘要】：研究目的：癲癇(epilepsy, EP)是神經(jīng)系統(tǒng)常見的慢性疾病之一,其中有30%左右的癲癇患者在經(jīng)過合理選用的抗癲癇藥物(antiepileptic drugs, AEDs)治療之后,仍不能有效控制發(fā)作,發(fā)展成為耐藥性癲癇,給患者及家人帶來沉重負擔。耐藥性癲癇的形成被認為是環(huán)境與遺傳因素共同作用的結(jié)果。近年來研究提示,主穹窿蛋白(major vault protein, MVP)、水通道蛋白4(aquaporin4, AQP4)以及內(nèi)向整流K+離子通道Kir4.1可能參與了癲癇的耐藥過程。癲癇的耐藥可能與基因單核苷酸多態(tài)(single nucleotide polymorphisms, SNPs)在不同地區(qū)的種族人群中存在關(guān)聯(lián)。本課題擬在中國漢族人群中探討MVP、AOP4、KCNJ10基因SNPs與部分性癲癇耐藥性是否相關(guān),為部分性癲癇的藥物個體化治療提供新的思路。 研究方法：依據(jù)國際抗癲癇聯(lián)盟(International League Against Epilepsy, ILAE)對癲癇分類和耐藥性癲癇的診斷標準,于中南大學湘雅醫(yī)院神經(jīng)內(nèi)科癲癇�？崎T診收集部分性癲癇病例510例,其中222例為耐藥組,288例為非耐藥組,配對選取健康人群對照206例,研究對象均為漢族,獲得知情同意后詳細詢問癲癇病史并進行臨床評估,抽取外周靜脈血提取全基因組DNA。從國際人類基因組單體型圖Hapmap數(shù)據(jù)庫通過Haploview (version4.2)軟件對中國漢族人群MVP、AOP4\KCNJ10基因SNP位點進行篩選。應用Sequenom MassARRAY SNP檢測方法對候選SNP位點進行基因分型。比較MVP、KCNJ10、AQP4基因SNP位點基因型頻率、等位基因頻率、連鎖不平衡(linkage disequilibrium, LD)及單倍型頻率在部分性癲癇耐藥組與非耐藥組、部分性癲癇與健康對照組間的差異,分析MVP、AOP4、KCNJ10基因SNPs是否在中國漢族人群中與部分性癲癇耐藥存在關(guān)聯(lián)。 研究結(jié)果： 1.部分性癲癇耐藥組相對于非耐藥組,發(fā)病起始年齡較早,服藥前的癲癇發(fā)作頻率相對較高,癲癇病程相對較長(P0.05)； 2.MVP基因4個SNP位點基因型頻率、等位基因頻率在部分性癲癇耐藥組與非耐藥組、部分性癲癇組與健康對照組之間未見明顯差異(P0.05)； 3.AQP4基因3個SNP位點、KCNJ10基因9個SNP位點的基因型頻率、等位基因頻率在部分性癲癇耐藥組與非耐藥組間未見明顯差異(P0.05),在特發(fā)部分性癲癇組與健康對照組間,KCNJ10rs1890532CG基因型在健康人群中頻率高于癲癇人群(OR=0.636,95%CI (0.409-0.989), P=0.045);但經(jīng)Bofferoni方法進行多重檢驗校正后P=0.405,組間比較未見明顯差異； 4)部分性癲癇耐藥組與非耐藥組在SNP位點LD分析中,MVP基因rs12149746、 rs1057451、rs9938630,AQP4基因rs1058424、 rs3763043、rs35931以及KCNJ10基因rs12122979、rs1186685.rs6690889位點間分別存在LD并形成單倍域(D’0.7且r20.4),組間單倍型頻率分析未見明顯差異(P0.05) 研究結(jié)論： 1.部分性癲癇發(fā)病年齡、服藥前發(fā)作頻率、病程長短可作為耐藥的風險評估指標； 2.MVP基因SNPs在中國漢族人群中可能與部分性癲癇的耐藥及易感性不相關(guān)； 3.AQP4基因和KCNJ10基因SNPs在中國漢族人群中可能與部分性癲癇的耐藥及易感性不相關(guān)。 5. MVP、AQP4、KCNJ10基因SNP位點單倍型在中國漢族人群中可能與部分性癲癇的耐藥不相關(guān)。
[Abstract]:Objective: epilepsy (epilepsy, EP) is one of the common chronic diseases of the nervous system, which has about 30% patients with epilepsy after antiepileptic drug selection (antiepileptic drugs, AEDs) after treatment, still can not effectively control the seizures, become resistant epilepsy, bring heavy burden to patients and their families. The formation of drug resistance epilepsy is considered the interaction of environmental and genetic factors. Recent studies suggest that major vault protein (major vault protein, MVP), aquaporin 4 (aquaporin4, AQP4) and inward rectifier K+ channels may be involved in the process of Kir4.1 resistant epilepsy. Epilepsy drug resistance and gene single nucleotide polymorphisms (single nucleotide polymorphisms, SNPs) association exists in different regions of the ethnic groups. In this study Chinese Han population of MVP, AOP4, SNPs and partial KCNJ10 gene Whether the drug resistance is associated with epilepsy provides a new way of thinking for the individualized treatment of drugs in partial epilepsy.
Research methods: according to the International League Against Epilepsy (International League Against Epilepsy, ILAE) on seizure classification and drug resistance epilepsy diagnosis standard in Xiangya Hospital of Central South University Department of neurology clinic collected partial epilepsy 510 cases, including 222 cases of drug resistant group, 288 cases of non resistance group, 206 normal subjects were chosen the object of study, all were Han nationality, after obtaining informed consent and asked in detail about the history of epilepsy and clinical assessment, extraction of genomic DNA. from the International HapMap database through the Hapmap Haploview peripheral venous blood samples (version4.2) software to China Han population MVP AOP4KCNJ10 SNP gene were selected. Using Sequenom MassARRAY SNP detection method. Genotyping of the candidate SNP sites. MVP, KCNJ10, AQP4 gene SNP genotype, allele frequencies, linkage The difference between linkage disequilibrium (LD) and haplotype frequency in partial epilepsy drug resistant group and non drug resistant group was between partial epilepsy and healthy control group. Whether MVP, AOP4 and KCNJ10 gene SNPs were associated with partial epilepsy drug resistance in Chinese Han population were analyzed.
The results of the study:
In the 1. part, the onset age of the epileptic drug resistance group was earlier than that of the non drug resistant group. The frequency of epileptic seizures before treatment was relatively high, and the duration of epilepsy was relatively long (P0.05).
The genotype frequencies and allele frequencies of 4 SNP loci in 2.MVP gene were not significantly different between the partial epilepsy group and the non drug resistant group. There was no significant difference between the partial epilepsy group and the healthy control group (P0.05).
3 SNP loci of 3.AQP4 gene, the genotype frequencies of 9 SNP loci of KCNJ10 gene, allele frequency in partial epilepsy resistant group and non resistance group, there was no significant difference between (P0.05), in idiopathic partial epilepsy group and the healthy control group, KCNJ10rs1890532CG genotype in the healthy population is higher than the frequency of epileptic patients (OR=0.636,95%CI (0.409-0.989), P=0.045); but the Bonferroni correction by P=0.405 Bofferoni method, comparison between groups showed no significant difference;
4) partial epilepsy resistant group and non resistance group analysis in the SNP locus in LD gene, MVP rs12149746, rs1057451, rs9938630, AQP4, rs3763043, rs35931, rs1058424 gene, KCNJ10 gene rs12122979, rs1186685.rs6690889 locus exists respectively and the formation of LD single domain (D 0.7 and r20.4), there was no significant difference between the analysis of haplotype frequencies between groups (P0.05)
The conclusions are as follows:
The age of the 1. sexual epilepsy, the frequency of the attack before taking medicine, the length of the disease can be used as the risk assessment index of the drug resistance.
The 2.MVP gene SNPs may not be related to the resistance and susceptibility of partial epilepsy in Chinese Han population.
The 3.AQP4 gene and the KCNJ10 gene SNPs may not be associated with resistance and susceptibility to partial epilepsy in Chinese Han population.
The haplotype of 5. MVP, AQP4, and KCNJ10 gene SNP loci may not be related to the resistance of partial epilepsy in Chinese Han population.

【學位授予單位】：中南大學
【學位級別】：博士
【學位授予年份】：2014
【分類號】：R742.1

【參考文獻】

相關(guān)期刊論文 前2條

1 ;SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci[J];Cell Research;2005年02期

2 陳英輝;趙永波;劉文文;咼登俊;王乃東;馬愛梅;;藥物難治性癲癇患者腦內(nèi)水通道蛋白-4的表達上調(diào)(英文)[J];Neuroscience Bulletin;2005年06期

，

本文編號：1677881