Alcohol Pharmacogenetics in Mexican Americans

描述（由申请人提供）：西班牙裔是美国增长最快的种族之一，截至2000年3月，西班牙裔占全国人口的12%，与其他种族背景（如高加索人和非洲裔美国人）相比，西班牙裔与酒精有关的问题比例更高。尽管如此，可能导致这种风险的遗传因素仍然知之甚少。在已经建立的研究基础设施的基础上，这个竞争性的延续申请将系统地探索和检查墨西哥裔美国人酗酒的遗传机制。这个正在进行的研究项目已经开始确定独特的遗传模式，这种模式可能在一定程度上导致这一人群中酗酒和酒精相关健康问题的风险增加。这包括(1)ALDH2*2（醛脱氢酶）和ADH2*2（醇脱氢酶）的等位基因频率极低；(2) ADH3*2和CYP2E1 c2（细胞色素P4502E1）等位基因比例较高；(3) ADH3*2、ADH2*1、DRD2（多巴胺受体-141C Del/Ins）和5-羟色胺转运蛋白基因相关多态性区（5-HTTLPR）与酒精中毒的相关性；(4) ADH3*2和ADH2*1等位基因与酗酒有较强的相关性；(5) DRD2 Taq1 A和1B等位基因与饮酒发病年龄的关系。在这个新的资助周期中，我们计划进一步追求和阐明这些发现的意义。具体来说，我们将(1)扩大我们的研究，纳入有酒精问题的墨西哥裔美国妇女；(2)进一步研究这些多态性在墨西哥裔美国人酒精中毒风险中的作用，以及它们之间潜在的相互作用；(3)检查这些风险与酒精中毒严重程度（即酗酒和早发性饮酒）的关系；(4)鉴定和确定墨西哥裔美国人与饮酒相关的DRD2单倍型，并评估单倍型与等位基因分析在描述导致酒精中毒的危险因素方面的相对优势。这项研究将是第一个系统地研究遗传因素如何调节墨西哥裔美国人的酒精依赖和滥用。这项研究的结果不仅有助于更好地了解墨西哥裔美国人的酒精使用和滥用情况，而且还有助于建立一个关于酒精药物遗传学的种族差异的知识库，以及可能导致这一少数群体中酗酒率高的机制。

DESCRIPTION (provided by applicant): Representing one of the fastest growing ethnic groups in the United States, Hispanics accounted for 12% of the nation's population by March 2000, and suffer from higher rates of alcohol related problems as compared with those from other ethnic backgrounds (e.g., Caucasians and African Americans). This notwithstanding, genetic factors that might contribute to such risks remain poorly understood. Building upon the research infrastructure that has been established, this competitive continuation application will systematically explore and examine genetic mechanisms for alcoholism in Mexican Americans. This ongoing research program has started to identify unique genetic patterns that might be in part responsible for the heightened risk for alcoholism and alcohol associated health problems in this population. These include (1) extremely low allele frequency for both ALDH2*2 (aldehyde dehydrogenase) and ADH2*2 (alcohol dehydrogenase); (2) a relatively high rate of ADH3*2 and CYP2E1 c2 (cytochrome P4502E1) alleles; (3) association of ADH3*2, ADH2*1, DRD2 (dopamine receptor -141C Del/Ins) and serotonin transporter gene-linked polymorphic region (5-HTTLPR) with alcoholism; (4) a strong association of ADH3*2 and ADH2*1 alleles with binge drinking; and (5) association of the DRD2 Taq1 A and 1B alleles with early age of onset for drinking. In this new funding cycle, we plan to further pursue and clarify the meaning of these findings. Specifically, we will (1) expand our study to include Mexican American women with alcohol problems; (2) further examine the role of these polymorphisms, as well as their potential interactions, in relation to risks for alcoholism in Mexican American populations; (3) examine the role of these risks in relationship with the severity of alcoholism i.e. binge drinking and early onset of drinking; (4) characterize and determine the haplotype of DRD2 in association with drinking in Mexican Americans, and assess the relative advantage of haplotype vs. allelic analysis in delineating risk factors contributory to the development of alcoholism. This study will be the first to systematically examine how genetic factors modulate alcohol dependence and abuse in Mexican Americans. Results derived from such a study should not only provide for a better understanding of alcohol use and abuse among Mexican Americans, but also contribute towards a knowledge base regarding ethnic differences in alcohol pharmacogenetics and mechanisms that might be responsible for the high rate of alcoholism in this minority population.