Mutation Screening of Nicotine and Alcohol Dependence

描述(申请人提供)：本项目的长期目标是 易患这两种疾病的个体DNA序列变异的鉴定 酒精和尼古丁依赖。酒精和尼古丁滥用的后遗症 代表着美国和其他地方的主要健康问题，包括对 各种癌症、心血管和肺部疾病的发展，如 以及增加自杀和其他死亡原因的风险以及 发病率。许多双胞胎、收养和家庭研究都证明了 是导致酗酒和酗酒的重要遗传因素 尼古丁依赖。更现代的研究表明，大量的 这种遗传责任的比例在这两种疾病之间分担。一个 各种生理、生化、损伤和动物模型研究 证明腹侧多巴胺能奖赏机制在 两者的自我管理和强化特点 物质。因此，从逻辑上讲，基因的变异涉及到 这些奖赏通路的功能或形成可以解释一部分或 所有由酒精和尼古丁依赖共同承担的遗传责任。这个 目前应用的目标是识别编码区和相关的DNA 多巴胺能奖赏相关候选基因的序列变异 既有尼古丁又有酒精依赖的人的神经通路。vbl.使用 变性高效液相色谱(DHPLC)检测序列 变异与标准定量传输失真分析 方法，300名尼古丁和酒精依赖者和他们的 将对双亲进行系统的DNA序列之间的关联测试 这些候选基因的变异与酒精和尼古丁的存在 依赖。发现这样的序列变异将具有重要的科学和 了解遗传因素对人类健康的影响 这些疾病的风险，开发新的药理和 这些疾病的其他治疗方法以及用于识别 处于这些疾病发展风险中的个人。

DESCRIPTION (provided by applicant): The long-term goal of this project is the identification of DNA sequence variations which predispose individuals to both alcohol and nicotine dependence. The sequelae of alcohol and nicotine abuse represent major health problems in the US and elsewhere including effects on the development of a variety of cancers, cardiovascular and lung diseases, as well as increasing the risk of suicide and other causes of mortality and morbidity. Many twin, adoption and family studies have demonstrated that there are important genetic contributions to the development of alcoholism and nicotine dependence. More modern studies demonstrate that a substantial proportion of this genetic liability is shared between these two disorders. A variety of physiological, biochemical, lesion and animal model studies have demonstrated the importance of ventral dopaminergic reward mechanisms in the self-administration and reinforcing characteristics of both of these substances. It follows logically, then, that variations in genes involved in the function or formation of these reward pathways may account for a portion or for all of the genetic liability shared by alcohol and nicotine dependence. The goal of the current application is to identify coding region and related DNA sequence variations in candidate genes associated with the dopaminergic reward pathways in individuals who have both nicotine and alcohol dependence. Using denaturing high-performance liquid chromatography (DHPLC) detection of sequence variation and standard and quantitative transmission distortion analytic approaches, three hundred nicotine and alcohol dependent individuals and their parents will be systematically tested for an association between DNA sequence variations in these candidate genes and the presence of alcohol and nicotine dependence. Finding such sequence variations will have important scientific and public health implications for understanding the genetic contributions to the risk for these disorders, for the development of novel pharmacological and other treatment approaches to these disorders and for the identification of individuals at risk for the development of these disorders.