UGT2B7基因多态性与丙戊酸血药浓度的相关性研究
摘要
目的：建立UGT2B7-268A>G的基因分型方法,确定其在中国汉族人群中的突变频率；研究UGT2B7-268A>G、G211T基因多态性对丙戊酸血药浓度的影响。
方法：收集248例于中南大学湘雅医院就诊的长期单用丙戊酸类药物癫痫患者的详细临床资料,其中男166例,女82例,建立包括患者基本信息、癫痫发作类型、发作时间、用药情况、治疗效果、肝肾功能及其他情况的详细档案库。所有患者于清晨服用丙戊酸类药物前空腹抽取外周静脉血2mL,测定稳态血药浓度,按照患者体重和日剂量将血药浓度标准化。从血细胞中提取基因组DNA,采用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)方法对丙戊酸代谢酶UGT2B7-268A>G、G211T进行基因型分析。通过多元线性回归分析患者年龄、体重指数、体重日剂量对血药浓度的影响,应用方差分析、卡方检验和配对t检验对实验数据进行统计学分析。
结果：248例患者的标准化血药浓度范围为：0.1320-23.2225μg·kg·ml-1·mg-1,性别、年龄、体重指数对丙戊酸标准化血药浓度无明显影响,体重日剂量与标准化血药浓度呈正相关。UGT2B7-268A>G、UGT2B7G211T等位基因的发生频率均符合Hardy-Weinberg平衡。UGT2B7-268A>G等位基因的A的分布频率为30.05%,G为69.95%,三种基因型血药浓度的方差分析F=5.477,P=0.005,结果显示三组间血药浓度存在显著性差异。继续做两两组间比较,野生型纯合子与杂合子、突变型纯合子与杂合子间血药浓度值无显著性差异,野生型纯合子A/A与突变型纯合子G/G组t检验,P值为0.048,差异具有统计学意义,野生型纯合子组的标准化血药浓度高于突变型纯合子组。UGT2B7 G21 1T等位基因G的分布频率为77.24%,T为22.58%,三种基因型血药浓度的方差分析F=3.832,P=0.23,三组间血药浓度差异不显著。
结论：本试验初步确证了UGT2B7-268A>G在中国癫痫人群的分布特征,研究结果显示UGT2B7-268A>G基因多态性对丙戊酸血药浓度有一定影响,A/A型患者浓度明显高于其他基因型；UGT2B7 G211T不同基因型对丙戊酸血药浓度的影响不显著。
Objectives:Establish a genotyping method of UGT2B7-268A>G to investigate its distribution features in Chinese population. Explore the effect of UGT2B7-268A> G、UGT2B7G211T gene polymorphism to valproic acid's serum drug concentration.
Methods:Collect the detailed clinical information of a total of 248 epilepsy patients who took long-term use of valproic acid drugs, male 166 cases and female 82 cases.Establish a data base including basic information, epilepsy type, fit time, drug use, treatment effect, liver and kidney function and so on. Steady serum concentration were monitored from 2mL peripheral blood drawed in the morning before the patients took valproic acid,all serum concentration were standardized according to patients weight and daily doses. Genome DNA were extracted from blood cells. The genotypes of UGT2B7-268A>G and UGT2B7G211T in all subjects were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.Statistical analyses were performed by multivariate linear regression one-way ANOVA,χ2 test and paired T-test.
Results:The standardized serum concentration of 248 patients are between 132.86μg·kg·ml-1·mg-1 to 23222.50μg·kg·ml-1·mg-1.There's no significant difference between gender, age and body mass index. Daily dose according to weight and standardized serum concentration were positively correlated.
The genetic polymorphisms of UGT2B7-268A>G and UGT2B7G211T genes were consistent with Hardy-Weinberg equilibrium.UGT2B7-268A>G allele frequency distribution A is 30.05%, G is 69.95%, genotype of AA. AG. GG have significant difference in serum concentration as variance analysis result showed (F =5.477, P=0.005).Further analysis of paired T test shows that, AA type has significant difference from GG type(P=0.048), serum concentration of AA type is much more higher than GG type, no significant difference between AA type and AG type, GG type and AG type either.
UGT2B7 G211T allele frequency distribution G is 77.24%, T is 22.58%, genotype of GG、GT and TT have no significant difference in standardized serum concentration.
Conclusion:This study reveals UGT2B7-268A>G gene polymorphism distribution in Chinese epilepsy population, the research results show that UGT2B7-268A>G might plan an important role in valproic acid's metabolism, and has certain effect to valproic acid's serum concentration, as genotype A/A is much more higher than others. Epilepsy patient with this genotype should be taken consider to adjust dose or treatment. UGT2B7 G211T gene polymorphism shows no significant difference in valproic acid's standardized serum concentration.
方法：收集248例于中南大学湘雅医院就诊的长期单用丙戊酸类药物癫痫患者的详细临床资料,其中男166例,女82例,建立包括患者基本信息、癫痫发作类型、发作时间、用药情况、治疗效果、肝肾功能及其他情况的详细档案库。所有患者于清晨服用丙戊酸类药物前空腹抽取外周静脉血2mL,测定稳态血药浓度,按照患者体重和日剂量将血药浓度标准化。从血细胞中提取基因组DNA,采用聚合酶链式反应-限制性片断长度多态性(PCR-RFLP)方法对丙戊酸代谢酶UGT2B7-268A>G、G211T进行基因型分析。通过多元线性回归分析患者年龄、体重指数、体重日剂量对血药浓度的影响,应用方差分析、卡方检验和配对t检验对实验数据进行统计学分析。
结果：248例患者的标准化血药浓度范围为：0.1320-23.2225μg·kg·ml-1·mg-1,性别、年龄、体重指数对丙戊酸标准化血药浓度无明显影响,体重日剂量与标准化血药浓度呈正相关。UGT2B7-268A>G、UGT2B7G211T等位基因的发生频率均符合Hardy-Weinberg平衡。UGT2B7-268A>G等位基因的A的分布频率为30.05%,G为69.95%,三种基因型血药浓度的方差分析F=5.477,P=0.005,结果显示三组间血药浓度存在显著性差异。继续做两两组间比较,野生型纯合子与杂合子、突变型纯合子与杂合子间血药浓度值无显著性差异,野生型纯合子A/A与突变型纯合子G/G组t检验,P值为0.048,差异具有统计学意义,野生型纯合子组的标准化血药浓度高于突变型纯合子组。UGT2B7 G21 1T等位基因G的分布频率为77.24%,T为22.58%,三种基因型血药浓度的方差分析F=3.832,P=0.23,三组间血药浓度差异不显著。
结论：本试验初步确证了UGT2B7-268A>G在中国癫痫人群的分布特征,研究结果显示UGT2B7-268A>G基因多态性对丙戊酸血药浓度有一定影响,A/A型患者浓度明显高于其他基因型；UGT2B7 G211T不同基因型对丙戊酸血药浓度的影响不显著。
Objectives:Establish a genotyping method of UGT2B7-268A>G to investigate its distribution features in Chinese population. Explore the effect of UGT2B7-268A> G、UGT2B7G211T gene polymorphism to valproic acid's serum drug concentration.
Methods:Collect the detailed clinical information of a total of 248 epilepsy patients who took long-term use of valproic acid drugs, male 166 cases and female 82 cases.Establish a data base including basic information, epilepsy type, fit time, drug use, treatment effect, liver and kidney function and so on. Steady serum concentration were monitored from 2mL peripheral blood drawed in the morning before the patients took valproic acid,all serum concentration were standardized according to patients weight and daily doses. Genome DNA were extracted from blood cells. The genotypes of UGT2B7-268A>G and UGT2B7G211T in all subjects were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay.Statistical analyses were performed by multivariate linear regression one-way ANOVA,χ2 test and paired T-test.
Results:The standardized serum concentration of 248 patients are between 132.86μg·kg·ml-1·mg-1 to 23222.50μg·kg·ml-1·mg-1.There's no significant difference between gender, age and body mass index. Daily dose according to weight and standardized serum concentration were positively correlated.
The genetic polymorphisms of UGT2B7-268A>G and UGT2B7G211T genes were consistent with Hardy-Weinberg equilibrium.UGT2B7-268A>G allele frequency distribution A is 30.05%, G is 69.95%, genotype of AA. AG. GG have significant difference in serum concentration as variance analysis result showed (F =5.477, P=0.005).Further analysis of paired T test shows that, AA type has significant difference from GG type(P=0.048), serum concentration of AA type is much more higher than GG type, no significant difference between AA type and AG type, GG type and AG type either.
UGT2B7 G211T allele frequency distribution G is 77.24%, T is 22.58%, genotype of GG、GT and TT have no significant difference in standardized serum concentration.
Conclusion:This study reveals UGT2B7-268A>G gene polymorphism distribution in Chinese epilepsy population, the research results show that UGT2B7-268A>G might plan an important role in valproic acid's metabolism, and has certain effect to valproic acid's serum concentration, as genotype A/A is much more higher than others. Epilepsy patient with this genotype should be taken consider to adjust dose or treatment. UGT2B7 G211T gene polymorphism shows no significant difference in valproic acid's standardized serum concentration.
引文
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