代谢、转运及效应通路相关基因多态性与丙戊酸钠治疗癫痫疗效的关联性研究

发布时间：2018-03-26 15:41

本文选题：癫痫　切入点：丙戊酸钠　出处：《中南大学》2014年硕士论文

【摘要】：目的：癫痫目前已有成熟的治疗药物和治疗方案,但在约三分之一的患者中抗癫痫药物疗效不佳,患者间疗效的差异可能由多个途径基因的多态性造成。丙戊酸钠作为治疗癫痫的常用一线药物,其临床疗效也存在较大的个体差异。本研究旨在分析丙戊酸钠代谢、转运和效应通路中各相关基因的多态性对于癫痫患者丙戊酸钠疗效的影响。方法：共入组201名癫痫患者,回访收集患者一年内发作次数作为疗效的评判指标。其中131名患者对丙戊酸钠敏感,另外70名患者耐药。选择丙戊酸钠代谢、转运和效应通路上的11个候选基因：ABCB1、CYP2C19、UGT2B7、GRIN2B、SCN1A、SCN2A、GABRA1、 GABRG2.GABRA6.ALDH5A1,ABAT,共24个SNP。运用MALDI-TOFMS法检测SNP的遗传变异,并分析各遗传变异和丙戊酸钠疗效之间的关系。应用logistic回归分析、t检验、卡方检验、多因子降维分析等统计方法进行统计学分析。结果：24个SNP等位基因的发生频率均符合Hardy-Weinberg平衡。药物转运蛋白,ABATrs1731017CT多态性与癫痫患者耐药表型相关(P=0.048,OR=0.271,95%可信区间=0.108-0.682)。药物受体蛋白,SCN2A rs2304016AG多态性与癫痫患者药物敏感表型有边缘显著相关性(P=0.09；OR=3.495,95%可信区间=1.418-8.618)。多因子降维分析显示最佳基因-基因交互作用组合为ABAT rs1731017同SCN2A rs2304016,有统计学意义(P0.0001；OR=3.6892,95%可信区间=1.9347-7.0347)。结论：中国汉族人群癫痫患者中,ABAT rs1731017变异和丙戊酸钠疗效显著相关,SCN2A rs2304016和丙戊酸钠疗效有边缘显著相关性。ABAT rs1731017和SCN2A rs2304016存在基因-基因交互作用,两者变异和丙戊酸钠疗效显著相关。
[Abstract]:Objective: there are mature drugs and treatments for epilepsy, but antiepileptic drugs are not effective in about 1/3 patients. The difference in efficacy between patients may be caused by polymorphism of multiple pathway genes. Sodium valproate, as a common first-line drug in the treatment of epilepsy, also has significant individual differences in clinical efficacy. The purpose of this study was to analyze the metabolism of sodium valproate. Effects of polymorphisms of genes involved in transport and response pathways on the efficacy of valproate in epileptic patients. Methods: 201 patients with epilepsy were enrolled in the study. The frequency of seizure in one year was collected as the index to evaluate the curative effect. Among them, 131 patients were sensitive to valproate, the other 70 patients were resistant to drugs, and sodium valproate metabolism was selected. Eleven candidate genes: ABCB1, CYP2C19, UGT2B7, GRIN2B, SCN1, GABRG2, GABRG2.GABRA6.ALDH5A1, ABAT24 SNPs were used to detect the genetic variation of SNP, and to analyze the relationship between genetic variation and valproate therapeutic effect. Logistic regression analysis and chi-square test were used to detect the genetic variation of SNP, and to analyze the relationship between the genetic variation and the efficacy of valproate sodium valproate. Statistical methods such as multi-factor dimensionality reduction analysis were analyzed statistically. Results: the frequency of 24 SNP alleles was consistent with the Hardy-Weinberg balance. The polymorphism of drug transporter ABATrs1731017CT was associated with the phenotype of drug resistance in epileptic patients. The multivariate dimensionality reduction analysis showed that the best combination of gene-gene interaction was ABAT rs1731017 and SCN2A rs2304016, with statistical significance of 1.9347-7.0347%. Conclusion: there is a significant correlation between the variation of ABAT rs1731017 and the efficacy of sodium valproate in Chinese Han nationality epilepsy patients. There is a marginal significant correlation between the efficacy of SCN2A rs2304016 and sodium valproate. There is a gene gene interaction between ABAT rs1731017 and SCN2A rs2304016. Both variations were significantly correlated with the efficacy of sodium valproate.
【学位授予单位】：中南大学
【学位级别】：硕士
【学位授予年份】：2014
【分类号】：R742.1

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