ALCOHOL PHARMACOGENETICS IN MEXICAN AMERICANS

描述（改编自申请人的摘要）：本申请的具体目的 该项目旨在分析细胞色素P4502E1（CYP2E1）对 酒精性肝病（ALD）的个体间易感性 墨西哥裔美国人长期目标是了解分子 ALD的发展和耐药性的潜在机制 墨西哥裔美国人CYP2E1基因的c2等位基因与 在某些民族中，ALD的发展。在墨西哥裔美国人中， 频率为16%。将采取四种方法来分析 ALD中的CYP2E1。首先，墨西哥裔美国ALD患者（200例受试者）将接受 招募并进行CYP2E1基因分型。用氯唑沙宗对CYP2E1进行表型分析 还将在正常志愿者和ALD患者的子集中进行 不同的等位基因。ALD、CYP2E1活性和 将确定基因型。乙醛脱氢酶（AlDH2）基因型 还将进行检查以评估酒精性肝脏病的其他可能原因。第二、 将通过正常表型检查乙醇对CYP2E1的诱导作用 携带不同等位基因的受试者和ALD患者。对于正常受试者， 在消耗乙醇之前和之后进行表型分型。为 ALD患者，表型将在受试者接受 戒酒基因型、诱发因素与遗传易感性的关系 将确定酒精的酶活性和ALD的发展。第三、 墨西哥裔美国人受试者（200例受试者）滥用酒精，但没有 ALD，将对CYP2E1和ADH 2基因进行基因分型。同样， 将在以下受试者中检查酒精对CYP2E1的诱导作用： 不同的等位基因第四，将通过PCR研究CYP2E1基因， 在基因型与给定的 表型或ALD的发展，以确定其他候选基因 这可能是导致ALD的原因。此外， 野生型和突变体泛素，负责降解CYP2E1， 将在对照、ALD和非ALD受试者中进行研究，以确定CYP2E1 活性主要在转录后水平上受到控制。数据 从这项研究中产生的将奠定基础，了解 在墨西哥裔美国人中，ALD的药物遗传学方面， 美国的少数民族。

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.