ALCOHOL PHARMACOGENETICS IN MEXICAN AMERICANS

描述(改编自申请人的摘要)：本报告的具体目的 本课题旨在分析细胞色素P4502E1(细胞色素P4502E1)在细胞周期中的作用。 酒精性肝病(ALD)的个体间易感性 墨西哥裔美国人。长期的目标是理解分子 肌萎缩侧索硬化症的发生和耐药机制 墨西哥裔美国人。CYP2E1基因的c2等位基因与 阿尔茨海默病在部分民族中的发展。在墨西哥裔美国人中，c2等位基因 频率为16%。我们将从四个方面来分析 肌萎缩侧索硬化症中的细胞色素P450-2E_1。首先，墨西哥裔美国ALD患者(200名受试者) 被招募并进行了CYP2E1的基因分型。氯唑沙宗用于细胞色素P450_2E_1的表型鉴定 也将在正常志愿者和ALD患者的子组中进行 有不同的等位基因。ALD、细胞色素P4502E_1活性和 基因分型将会确定。乙醛脱氢酶(ALDH2)基因 也将接受检查以评估其他可能导致ALD的原因。第二, 乙醇对细胞色素P450_2E_1的诱导性将通过正常表型进行检测 受试者和携带不同等位基因的ALD患者。对于正常受试者， 表型鉴定将在饮用乙醇之前和之后进行。对于 ALD患者，表型将在受试者前后进行测定 戒酒。基因分型与诱导性的关系 酒精引起的酶活性和ALD的发展将被测定。第三, 墨西哥裔美国受试者(200名受试者)酗酒，但没有 ALD，将对CYP2E1和ADH2基因进行基因分型。同样， 酒精对CYP2E1的诱导性将在以下受试者中进行检测 不同的等位基因。第四，将用聚合酶链式反应和聚合酶链式反应来研究细胞色素P421基因 基因既不与给定基因相关的受试者的测序 表型或ALD的发展，以确定其他候选基因 这可能是ALD的原因。此外，还出现了 野生型和突变型泛素，它负责降解CYP2E1， 将在对照组、ALD和非ALD受试者中进行研究，以确定CYP2E1是否 活性主要控制在转录后水平。数据 这项研究产生的数据将为理解 墨西哥裔美国人ALD的药物遗传学方面，增长最快 美国的少数民族人口。

DESCRIPTION (Adapted from the applicant's abstract): The specific aim of this project is to analyze the contribution of cytochrome P4502E1 (CYP2E1) to interindividual susceptibility to alcoholic liver disease (ALD) in Mexican-Americans. The long-term objective is to understand the molecular mechanisms underlying the development of, and the resistance to, ALD in Mexican-Americans. The c2 allele of the CYP2E1 gene is associated with the development of ALD in some ethnic groups. In Mexican-Americans, the c2 allele frequency is 16 percent. Four approaches will be taken to analyze the role of CYP2E1 in ALD. First, Mexican-American ALD patients (200 subjects) will be recruited and genotyped for CYP2E1. Phenotyping of CYP2E1 using chlorzoxazone will also be performed in a sub-set of both normal volunteers and ALD patients with different alleles. The association among ALD, CYP2E1 activity, and genotype will be determined. The genotype of aldehyde dehydrogenase (AlDH2) will also be examined to assess other another possible cause of ALD. Second, the inducibility of CYP2E1 by ethanol will be examined by phenotyping normal subjects and ALD patients who carry different alleles. For the normal subjects, phenotyping will be performed before and after consumption of ethanol. For the ALD patients, phenotype will be determined before and after the subjects have abstained from drinking. The relationship among genotype, inducibility of enzyme activity by alcohol, and development of ALD will be determined. Third, Mexican- American subjects (200 subjects) who abuse alcohol, but do not have ALD, will be genotyped for the CYP2E1 and ADH2 genes. Likewise, the inducibility of CYP2E1 by alcohol will be examined in subjects who have different alleles. Fourth, the CYP2E1 gene will be studied by PCR and sequencing in subjects whose genotype is associated with neither a given phenotype nor the development of ALD in order to identify other candidate genes that may be accounted for the cause of ALD. In addition, the presence of wild-type and mutant ubiquitin, which is responsible for degradation of CYP2E1, will be studied in control, ALD, and non-ALD subjects to determine if CYP2E1 activity is mainly controlled at the post-transcriptional level. The data generated from this study will lay the foundation for understanding the pharmacogenetic aspects of ALD in Mexican-Americans, the fastest growing minority population in the United States.