中国藏族人群CYP2D6基因多态性分析研究
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摘要
药物基因组学是研究与药物代谢相关基因的多态性与药物反应关系的学科。细胞色素P450超家族是人体重要的I相药物代谢酶,参与很多种内源性和外源性物质的代谢反应。CYP2D6是一种重要的药物代谢酶,主要在肝脏中表达,虽然含量比其他亚家族低,但是参与了市场上20%-25%药物的代谢,包括精神安定药、抗心律失常药、镇痛药、抗抑郁药、止吐药以及一些抗癌药等。
CYP2D6的酶活性会受到很多因素的影响,比如遗传因素、年龄、身体状况、饮食习惯等,CYP2D6具有多态性,可以导致酶活性的丧失、降低或者增高,从而影响药物的代谢,目前有70多种不同的CYP2D6基因突变被报道,常见的很大程度降低酶活性的等位基因有CYP2D6*10、CYP2D6*17和CYP2D6*41。CYP2D6*10有两个点突变,主要存在于亚洲人群中,是造成黄种人为中间代谢者(IMs)的主要因素,而在高加索人群中比较少见,频率低于2%。所以,对于CYP2D6基因多态性的研究对于临床用药,提高药物的疗效及用药安全性有重要意义,进而可以为药物基因组学研究提供理论依据。
目前,对于中国汉族人群CYP2D6多态性研究已有报道,中国是一个地域辽阔、多民族的国家,而藏族是人数较多的少数民族之一,一些重要基因的多态性可能与汉族人群有所不同。所以,本实验的研究对象是西藏自治区95例藏族健康人,用DNA直接测序的方法,对CYP2D6基因的启动区、外显子、内含子及3'-UTR测序。
研究结果主要有以下几个方面：在藏族人群中,一共检测到了51个单核苷酸突变位点,其中有12个新位点；分析统计了西藏自治区藏族人群CYP2D6等位基因,主要类型是CYP2D6*1、CYP2D6*2、CYP2D6*10、CYP2D6*34和CYP2D6*41,频率较高是等位基因是*1(野生型)、*2和*10,分别为31.4%,30.4%和33.6%；通过Haploview分析了主要SNPs间的连锁不平衡和单倍型；将本研究得到的我国西藏自治区藏族人群CYP2D6基因多态性和其他民族种族进行对比,发现存在较大的差异。
本实验对我国西藏藏族人群CYP2D6基因多态性的研究,是首次对藏族人群CYP2D6基因遗传多态性的全面检测和分析,对于建立我国少数民族CYP2D6基因多态性数据库,为药物基因组学研究最终实现个体化治疗提供了理论依据。
Pharmacogenetics is a study of how genetic polymorphism related to drug metabolism works with drug efficacy. Cytochrome P450 super family is the important phasel drug metabolizing enzyme which involves in the metabolism of many endogenous and exogenous substrates. CYP2D6 exists in the liver, metabolizes up to 20%-25% of the prescribed drugs including many neuroleptic, anti-arrhythmic, analgesics, antidepressants, antiemetics and anticancer drugs.
The enzyme activity of C YP2D6 would be influenced by a lot of factors, such as genetic differences, ages, physical conditions and life style, ect. Polymorphism of the gene coding CYP2D6 can lead to different levels expressions of enzyme activity, completely loss, decrease or increase which affects the metabolism of drugs. More than 70 different alleles of CYP2D6 have been described up to date, the common alleles decreasing the enzyme activity greatly are CYP2D6*10, CYP2D6* and CYP2D6*41. For the Asian groups, allele CYP2D6*10 is the most common one which contains two point mutations explaining the main cause of intermediate metabolizers among the yellow-skinned people, while it is rarely found in the Caucasians. Therefore, studying of CYP2D6 polymorphism is clinically helpful to evaluate drug safety and efficacy, and then provide a theory basis for pharmcogenetic research.
There have been some studies on the polymorphism of CYP2D6 in the Chinese Han population. China is a nation of great land mass and large population. Tibetan, as one of the minorities, some of the important gene polymorphic sites may vary with Chinese Han population. In this study, we systematically screened the polymorphisms of the whole CYP2D6 gene, including the 5'flanking region, all exons, and all introns, in the Chinese Tibetan, sample of 95 healthy subjects from the Tibet autonomous region.
The results of this study:In Chinese Tibetan population, a total of 51 different genetic polymorphisms were detected in the CYP2D6 gene, including 12 novle ones; We analyzed the CYP2D6 alleles and genotype frequencies, the main alleles were CYP2D6*1, CYP2D6*2, CYP2D6*10, CYP2D6*34 and CYP2D6*41, the most frequent alleles were the allele*1,*2 and*10, occur at frequencies of 31.4,30.4and 33.6%, respectively; We investigated the LD pattern and haplotype construction of this gene in this population by Haploview; We also compared frequencies of CYP2D6 alleles and genotypes with those of other national and ethnic populations, the results indicate significant differences in different populations.
This study is the first one which takes a fully analysis on the genetic polymorphism of CYP2D6 in the Chinese Tibetan and helps build a database of CYP2D6 alleles and genotype frequency among minorities as well as provides a theory basis for eventually individualized therapy.
CYP2D6的酶活性会受到很多因素的影响,比如遗传因素、年龄、身体状况、饮食习惯等,CYP2D6具有多态性,可以导致酶活性的丧失、降低或者增高,从而影响药物的代谢,目前有70多种不同的CYP2D6基因突变被报道,常见的很大程度降低酶活性的等位基因有CYP2D6*10、CYP2D6*17和CYP2D6*41。CYP2D6*10有两个点突变,主要存在于亚洲人群中,是造成黄种人为中间代谢者(IMs)的主要因素,而在高加索人群中比较少见,频率低于2%。所以,对于CYP2D6基因多态性的研究对于临床用药,提高药物的疗效及用药安全性有重要意义,进而可以为药物基因组学研究提供理论依据。
目前,对于中国汉族人群CYP2D6多态性研究已有报道,中国是一个地域辽阔、多民族的国家,而藏族是人数较多的少数民族之一,一些重要基因的多态性可能与汉族人群有所不同。所以,本实验的研究对象是西藏自治区95例藏族健康人,用DNA直接测序的方法,对CYP2D6基因的启动区、外显子、内含子及3'-UTR测序。
研究结果主要有以下几个方面：在藏族人群中,一共检测到了51个单核苷酸突变位点,其中有12个新位点；分析统计了西藏自治区藏族人群CYP2D6等位基因,主要类型是CYP2D6*1、CYP2D6*2、CYP2D6*10、CYP2D6*34和CYP2D6*41,频率较高是等位基因是*1(野生型)、*2和*10,分别为31.4%,30.4%和33.6%；通过Haploview分析了主要SNPs间的连锁不平衡和单倍型；将本研究得到的我国西藏自治区藏族人群CYP2D6基因多态性和其他民族种族进行对比,发现存在较大的差异。
本实验对我国西藏藏族人群CYP2D6基因多态性的研究,是首次对藏族人群CYP2D6基因遗传多态性的全面检测和分析,对于建立我国少数民族CYP2D6基因多态性数据库,为药物基因组学研究最终实现个体化治疗提供了理论依据。
Pharmacogenetics is a study of how genetic polymorphism related to drug metabolism works with drug efficacy. Cytochrome P450 super family is the important phasel drug metabolizing enzyme which involves in the metabolism of many endogenous and exogenous substrates. CYP2D6 exists in the liver, metabolizes up to 20%-25% of the prescribed drugs including many neuroleptic, anti-arrhythmic, analgesics, antidepressants, antiemetics and anticancer drugs.
The enzyme activity of C YP2D6 would be influenced by a lot of factors, such as genetic differences, ages, physical conditions and life style, ect. Polymorphism of the gene coding CYP2D6 can lead to different levels expressions of enzyme activity, completely loss, decrease or increase which affects the metabolism of drugs. More than 70 different alleles of CYP2D6 have been described up to date, the common alleles decreasing the enzyme activity greatly are CYP2D6*10, CYP2D6* and CYP2D6*41. For the Asian groups, allele CYP2D6*10 is the most common one which contains two point mutations explaining the main cause of intermediate metabolizers among the yellow-skinned people, while it is rarely found in the Caucasians. Therefore, studying of CYP2D6 polymorphism is clinically helpful to evaluate drug safety and efficacy, and then provide a theory basis for pharmcogenetic research.
There have been some studies on the polymorphism of CYP2D6 in the Chinese Han population. China is a nation of great land mass and large population. Tibetan, as one of the minorities, some of the important gene polymorphic sites may vary with Chinese Han population. In this study, we systematically screened the polymorphisms of the whole CYP2D6 gene, including the 5'flanking region, all exons, and all introns, in the Chinese Tibetan, sample of 95 healthy subjects from the Tibet autonomous region.
The results of this study:In Chinese Tibetan population, a total of 51 different genetic polymorphisms were detected in the CYP2D6 gene, including 12 novle ones; We analyzed the CYP2D6 alleles and genotype frequencies, the main alleles were CYP2D6*1, CYP2D6*2, CYP2D6*10, CYP2D6*34 and CYP2D6*41, the most frequent alleles were the allele*1,*2 and*10, occur at frequencies of 31.4,30.4and 33.6%, respectively; We investigated the LD pattern and haplotype construction of this gene in this population by Haploview; We also compared frequencies of CYP2D6 alleles and genotypes with those of other national and ethnic populations, the results indicate significant differences in different populations.
This study is the first one which takes a fully analysis on the genetic polymorphism of CYP2D6 in the Chinese Tibetan and helps build a database of CYP2D6 alleles and genotype frequency among minorities as well as provides a theory basis for eventually individualized therapy.
引文
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