ALCOHOL PHARMACOGENETICS IN MEXICAN AMERICANS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。拟议项目的主要重点是确定墨西哥裔美国人酗酒的遗传风险因素。本研究选择的基因属于两大类：（1）控制酒精如何分解和从体内消除的基因，以及（2）与酒精作用和/或酒精成瘾潜力相关的基因（即。多巴胺、血清素和GABA）。由于涉及酒精使用和成瘾的风险因素很可能是由于许多不同的原因，这似乎是一个合理的方法。通过同时检查这两类基因，我们的目标不仅是描述墨西哥裔美国人的基因分布，这些基因在其他人群中已得到很好的表征，并发现与饮酒行为，酒精成瘾和酒精相关的医疗问题有关，而且还探索这两类基因在酗酒中的相互作用。此外，由于墨西哥裔美国女性酗酒问题严重，而且妇女更容易受到与酒精有关的伤害，因此将妇女包括在内至关重要。虽然我们并不认为在非酒精人群中，男性和女性的某个基因的频率是不同的，但我们确实推测，如果男女酗酒的严重程度相同，那么女性的遗传与酗酒之间的联系可能比男性更强，因为女性性别是饮酒的保护因素。因此，本申请的中心主题是确定墨西哥裔美国人酗酒的遗传风险因素。我们将讨论这些遗传因素是如何相互关联的，吸烟如何调节酗酒的遗传因素，以及性别如何影响遗传关联。如上所述，除了酒精中毒，收集的数据还将使我们能够解决酒精相关问题的其他方面，包括种族差异，饮酒行为和模式，临床特征和潜在的酒精性肝病。 该研究包括1200名受试者，分为两组：酒精组和非酒精组，每组包括相同数量的男性和女性（每组n = 300）。 只有那些具有相同墨西哥裔美国人背景的人将被纳入研究，这被定义为有3/4的祖父母是墨西哥遗产。 在获得知情同意后，将使用简要筛选表筛选潜在受试者，以获取信息，确定其是否有资格参加研究。这些信息将包括人口统计信息（例如，种族、性别和年龄）、饮酒习惯、吸烟和其他可能成瘾的物质的使用、精神病史和病史。将邀请通过筛选的受试者进行初始评估。将获得详细的病史和精神病史，包括使用和滥用酒精和其他物质。酗酒者也将接受采访，使用几种仪器，也将抽血进行遗传研究。访谈期间使用的工具包括评估酒精滥用和依赖以及相关精神障碍的身体、心理社会和精神表现的问卷（酒精中毒遗传学半结构化评估（SSAGA-II）），以及评估酒精成瘾不同方面严重程度的自填问卷（酒精依赖严重程度问卷（SADQ））。然后将进行体格检查和实验室检查（全血细胞计数、生化检查、肝功能检查、血清抗核抗体、丙型肝炎抗体、B型肝炎表面抗原、尿液分析和尿液毒理学筛查）。在该阶段，将从每例受试者中采集总计70 ml血液。将使用10 ml血液进行DNA提取和基因分型。将采集另外20 ml血液储存，作为额外DNA提取的备份。血液和尿液检查将在我们的NIH资助的一般临床研究中心（GCRC）进行。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The primary focus of the proposed project is to identify the genetic risk factors for alcoholism in Mexican Americans. The genes selected for this study belong to two major categories: (1) those controlling how alcohol is broken down and eliminated from the body and (2) those associated with the action of alcohol and/or the potential for addiction to alcohol (ie. dopamine, serotonin and GABA ). As the risk factors involved in alcohol use and addiction are most likely due to a number of different reasons, this appears to be a reasonable approach. With the simultaneous examination of genes from both categories, we aim at not only describing the distribution in Mexican Americans of genes that have been well characterized in other populations and found to be associated with drinking behavior, alcohol addiction and alcohol related medical problems, but also to explore the interaction of those two categories of genes in alcoholism. Furthermore, it is crucial to include women because of the serious drinking problem in female Mexican Americans and because women are more susceptible to alcohol related injury. Although we do not anticipate that the frequency of a certain gene is different between men and women in the non-alcoholic population, we do speculate that a stronger association between genetics and alcoholism might be found in women than men if both genders have the same severity of alcoholism, since female gender is a protecting factor for drinking. Therefore, the central theme of this application is to identify the genetic risk factors for alcoholism in Mexican Americans. We will address how these genetic factors are interrelated, how smoking modulate genetic factors for alcoholism, and how gender affects genetic association. As mentioned above, besides alcoholism, the data collected would also allow us to address other aspects of alcohol related problem including ethnic variation, alcohol drinking behavior and pattern, clinical profile and potentially alcoholic liver disease. The proposed study includes 1200 subjects, divided into two groups: an alcoholic group and a non-alcoholic group, with each group comprising equal numbers of males and females (n = 300 each. Only those with homogeneous Mexican American backgrounds will be included in the study, this is defined as having 3 out 4 grandparents who are of Mexican heritage. After obtaining informed consent, potential subjects will be screened using a brief screening form to elicit information to establish their eligibility for the study. These will include information on demographics (e.g., ethnicity, gender and age), alcohol drinking habits, and usage of cigarettes and other substances of addictive potential, psychiatric and medical history. Subjects passing the screening will be invited for the initial assessment. Detailed medical and psychiatric history, including the use and abuse of alcohol and other substances, will be obtained. Alcoholic subjects will also be interviewed using several instruments and will also have blood drawn for genetic studies. The instruments to be used during the interview include questionnaires to assess the physical, psychosocial and psychiatric manifestations of alcohol abuse and dependence and related psychiatric disorders (The Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA-II), and a self administered questionnaire to assess the severity of different aspects of alcohol addiction (Severity of Alcohol Dependence Questionnaire (SADQ). Physical examination and laboratory tests (complete blood counts, chemistry panel, liver function tests, serum antinuclear antibody, hepatitis C antibody, hepatitis B surface antigen, urine analysis and urine toxicology screen) will then be performed. During this session, a total of 70 ml of blood will be obtained from each subject. Ten ml of blood will be used for DNA extraction and genotyping. Another twenty ml of blood will be collected for storage as backup for additional DNA extraction. Blood and urine tests will be done in our NIH funded General Clinical Research Center (GCRC).