西南地区儿童CYP3A4基因多态性分析与耐药性癫痫相关性研究

发布时间：2018-03-13 04:31

本文选题：儿童　切入点：耐药性癫痫　出处：《重庆医科大学》2012年硕士论文　论文类型：学位论文

【摘要】：第一部分西南地区儿童CYP3A4基因多态性分析研究目的对西南地区儿童CYP3A4~*18A、CYP3A4~*1G基因多态性进行分析，探讨其与该地区癫痫耐药的相关性。方法应用聚合酶链反应-限制性片段长度多态性技术，共检测238例儿童的CYP3A4~*18A、CYP3A4~*1G基因型频率和等位基因频率，其中耐药性癫痫组儿童（耐药组）83例、药物治疗有效组儿童（有效组）87例、健康儿童组（正常对照组）68例。结果（1）CYP3A4~*18A在耐药组中分布野生纯合子93%、突变杂合子7%，等位基因野生型96%、突变型4%；有效组、正常组野生纯合子100%，未发现突变。耐药组CYP3A4~*18A多态性的突变杂合子基因型频率及突变型等位基因频率高于有效组，差异有显著意义(P0.05)，耐药组与正常组基因型频率及等位基因频率比较，差异无显著意义(P0.05)。（2）CYP3A4~*1G野生纯合子在耐药组、有效组、正常组频率分别为47%、45%、50%；突变杂合子频率分别为46%、49%、43%；突变纯合子频率为7%、6%、7%。等位基因野生型频率分别为70%、70%、71%，突变型频率分别为30%、30%、29%。3组基因型频率及等位基因频率差异均无显著意义(P0.05)。结论（1）西南地区儿童CYP3A4~*18A基因多态性可能与癫痫耐药存在一定的相关性，筛查CYP3A4~*18A基因型是指导抗癫痫药物的选择，判断、预测其治疗效果的重要方法之一。（2）初步研究显示CYP3A4~*1G基因多态性与西南地区儿童癫痫耐药相关性不大，更准确的结论有待进一步扩大样本量来进行深入研究。第二部分CYP3A4基因多态性与西南地区儿童耐药性癫痫相关性研究目的（1）分析83例西南地区儿童耐药性癫痫的临床特征，探讨发生耐药的可能原因，以便及时调整治疗方案，改善预后。（2）进一步研究CYP3A4~*1G在不同发作类型、不同病因的癫痫儿童中的分布，，探讨其与药物治疗效果的相关性。方法收集2010年5月至2011年8月重庆医科大学附属儿童医院神经内科门诊诊断为药物IE患儿（耐药组）83例，药物有效患儿（有效组）87例，采取现场调查方式收集患儿性别、年龄、首次发病年龄，发作形式、发作次数，治疗情况，神经系统发育情况，脑电图、影像学结果等临床资料，采用病例对照分析方法对耐药组和有效组临床资料进行比较分析。应用聚合酶链反应-限制性片段长度多态性技术检测两组患儿CYP3A4~*1G基因多态性。结果（1）耐药组与有效组相比，1岁之前发病率、局灶性和发作类型无法确定者，有结构性和代谢性病因者，其影像学异常及脑电图异常改变几率明显增高。（2）在不同发作类型的癫痫儿童中CYP3A4~*1G基因型的分布差异无显著意义(P0.05)。（3）在遗传性或者未知病因患儿中，耐药组突变纯合子及突变等位基因频率明显高于有效组，差异均有统计学意义(P0.05)，在结构性和代谢性病因患儿中，2组基因型及等位基因频率差异均无显著意义(P0.05)。结论（1）IE患儿具有如下特点：发病年龄早，发作类型以局灶性和无法确定发作类型为主，病因以结构性和代谢性异常为主，影像学和脑电图异常改变多，应用两种及以上的抗癫痫药物组合者疗效差。（2）CYP3A4~*1G基因型与不同发作类型的癫痫儿童对抗癫痫药物治疗反应相关性不明显。（3）CYP3A4~*1G突变纯合子可能与遗传性或者未知病因癫痫患儿耐药具有一定的相关性。在遗传性或者未知病因患儿中，筛查CYP3A4~*1G基因型是指导抗癫痫药物选择，并判断、预测抗癫痫治疗效果的重要方法之一。
[Abstract]:Analysis of CYP3A4 gene polymorphism in children in the first part of the southwest region
objective
The polymorphism of CYP3A4~*18A and CYP3A4~*1G gene in the children of Southwest China was analyzed and the correlation with the drug resistance of epilepsy in this area was discussed.
Method
Restriction fragment length polymorphism polymerase chain reaction, were detected in 238 cases of children CYP3A4~*18A, CYP3A4~*1G genotype frequency and allele frequency among drug resistant epilepsy children (resistance group) 83 cases, effective drug treatment group (effective group) 87 cases, healthy children group (normal control group) 68 cases.
Result
(1) the distribution of wild homozygous CYP3A4~*18A in the resistant group 93%, heterozygous mutations in 7% alleles, 96% wild type and mutant 4%; effective group, normal group of wild homozygous 100% mutations were found. Heterozygous genotype frequency resistance group CYP3A4~*18A polymorphism and mutant allele frequency is higher than the effective group, the difference was significant (P0.05) compared with the normal group, group of drug resistant genotype and allele frequencies, no significant difference (P0.05).
(2) CYP3A4~*1G Nobu Juriko in the resistant group, group, normal group frequencies were 47%, 45%, 50%; heterozygote frequencies were 46%, 49%, 43%; homozygote frequency was 7%, 6%, 7%. allele of wild type were 70%, 70%, 71%, mutation frequencies were 30% 30%, 29%.3 group, genotype and allele frequencies were not significant (P0.05).
conclusion
(1) there is a certain correlation between CYP3A4~*18A gene polymorphism and epilepsy drug resistance in Southwest China. Screening CYP3A4~*18A genotype is an important way to guide the selection of antiepileptic drugs, to predict and predict the therapeutic effect.
(2) preliminary studies show that CYP3A4~*1G gene polymorphism is not associated with drug resistance in children in Southwest China. More accurate conclusions need further expansion of sample size for further research.
Study on the relationship between the second part CYP3A4 gene polymorphism and the resistance to epilepsy in children in Southwest China
objective
(1) to analyze the clinical characteristics of 83 cases of drug-resistant epilepsy in the children of Southwest China, and to explore the possible causes of drug resistance in order to adjust the treatment plan in time and improve the prognosis.
(2) to further study the distribution of CYP3A4~*1G in children with different types of seizures and different causes of epilepsy, and to explore the correlation with the effect of drug treatment.
Method
The children's Hospital Affiliated to Medical University Of Chongqing from May 2010 to August 2011 in neurology clinic diagnosed IE patients (drug resistant group) 83 cases, effective in children with drug (effective group) 87 cases, take the field survey collected with gender, age, onset age, seizure type, the number of attacks, treatment, nervous system development, EEG, clinical the results of imaging data, a case-control analysis of drug resistant group and effective group. The clinical data were compared and analyzed. The application of polymerase chain reaction restriction fragment length polymorphism technique was used to detect CYP3A4~*1G gene polymorphism in two groups.
Result
(1) compared with the effective group, the incidence rate of 1 years old group was significantly higher than that of the effective group.
(2) there was no significant difference in the distribution of CYP3A4~*1G genotypes among epileptic children with different types of seizures (P0.05).
(3) in hereditary or unknown etiology in children with homozygous resistant group and mutation allele frequency was significantly higher than the effective group, the differences were statistically significant (P0.05), in patients with structural and metabolic etiology, gene frequency genotype and the differences between the 2 groups was not significant (P0.05).
conclusion
(1) IE children have the following characteristics: the onset age is early, the type of seizure is mainly localized and uncertain, and the main causes are structural and metabolic abnormalities. There are many abnormal changes in imaging and EEG. The combination of two or more antiepileptic drugs has poor efficacy.
(2) the relationship between CYP3A4~*1G genotypes and epileptic children with different types of seizures is not significant.
(3) the homozygous CYP3A4~*1G mutation may have certain correlation with hereditary or unknown etiology in children with epilepsy. Drug resistance in hereditary or unknown etiology in children with screening of CYP3A4~*1G genotype is to guide the selection of anti epileptic drugs, and judge, one of the most important methods to predict anti epilepsy treatment effect.

【学位授予单位】：重庆医科大学
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R742.1

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