Alcohol Pharmacogenetics in Mexican Americans

描述(申请人提供)：拉美裔美国人是美国增长最快的种族群体之一，到2000年3月，拉美裔美国人占全国人口的12%，与其他种族背景的人(如高加索人和非裔美国人)相比，他们遭受与酒精有关的问题的比率更高。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，这项竞争性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。这项正在进行的研究计划已经开始识别独特的基因模式，这些模式可能在一定程度上导致了酒精中毒和与酒精相关的健康问题的风险增加。这些因素包括：(1)ALDH2*2(乙醛脱氢酶)和ADH2*2(酒精脱氢酶)等位基因频率极低；(2)ADH3*2和细胞色素P4502E1等位基因频率较高；(3)ADH3*2、ADH2*1、DRD2(多巴胺受体-141C DEL/INS)和5-羟色胺转运体基因连锁多态区域(5-HTTLPR)与酗酒有关；(4)ADH3*2和ADH2*1等位基因与酗酒有很强的相关性；以及(5)DR2Taq1A和1B等位基因与饮酒的早期发病相关。在这个新的筹资周期中，我们计划进一步探讨和澄清这些调查结果的意义。具体地说，我们将(1)扩大我们的研究范围，以包括有酒精问题的墨西哥裔美国女性；(2)进一步研究这些基因多态及其潜在的交互作用，与墨西哥裔美国人中酗酒的风险；(3)研究这些风险与酒精中毒的严重程度，即酗酒和过早饮酒之间的作用；(4)表征和确定DRD2与墨西哥裔美国人饮酒有关的单倍型，并评估单倍型分析与等位基因分析在确定导致酒精中毒发展的风险因素方面的相对优势。这项研究将首次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应该有助于更好地了解墨西哥裔美国人中酒精的使用和滥用，而且还应该有助于建立一个关于酒精药物遗传学中的种族差异以及可能导致这一少数群体酒精中毒率高的机制的知识库。

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.