GENETICS OF ALCOHOL SENSITIVITY

酒精敏感性的遗传学

• 批准号: 3112265
• 负责人: SHOZO YOKOYAMA
• 金额: $ 16.41万
• 依托单位: SYRACUSE UNIVERSITY AT SYRACUSE
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-01 至 1993-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3112265
• 关键词: acetaldehyde; alcohol dehydrogenase; alcoholism /alcohol abuse; alleles; biochemical evolution; disease /disorder proneness /risk; drug metabolism; endonuclease; enzyme structure; gel electrophoresis; genetic library; genetic manipulation; genetic polymorphism; human genetic material tag; human population genetics; human tissue; molecular cloning; molecular genetics; molecular pathology; nucleic acid sequence; polymerase chain reaction; statistics /biometry

In the human liver, ethanol is degraded by dimeric alcohol dehydrogenase (ADH) to acetaldehyde (AcH) and then by tetrameric aldehyde dehydrogenase (ALDH) with the subsequent production of acetate, and finally Co 2 and H20. The genetic polymorphisms at the ADH and ALDH loci are suspected to have importance in determining the degree of susceptibility to ethanol. Thus, to understand the genetics of alcohol sensitivity and alcoholism, it is important to evaluate the molecular structure of the ADH and ALDH genes. As an initial step toward that end, we plan to characterize different ADH genes at the molecular level. So far, molecular characterization of the ADH genes has been mostly at the cDNA level and only the genomic structure of the ADH2 locus has been elucidated. As an initial step toward the understanding of the genetics of alcohol sensitivity, we propose to characterize all ADH genes, including not only those at the ADH1, ADH2, and ADH3 loci of class I but also those of the class II and III loci. Using DNA from the PI, we have isolated partial genomic clones not only of all these ADH genes but also of a new ADH gene which was previously unknown. In order to characterize all of these ADH genes completely, we propose to construct a library using the same genomic DNA, screen it, and perform DNA sequencing. By using the DNA sequence data obtained, we plan to study DNA polymorphism at informative regions at each ADH locus by the method of polymerase chain reaction and direct genomic sequencing. These data and other published data will also be used to study the pattern of ADH gene differentiation.

在人肝脏中，乙醇被二聚体醇脱氢酶降解 （ADH）至乙醛（ACH），然后通过四醛醛脱氢酶 （ALDH）随后产生乙酸盐，最后是CO 2和H20。 怀疑ADH和ALDH基因座的遗传多态性 确定乙醇易感程度的重要性。因此， 了解酒精敏感性和酒精中毒的遗传学，这是 评估ADH和ALDH基因的分子结构很重要。作为 朝这一目的迈出的第一步，我们计划表征不同的ADH 分子水平的基因。 到目前为止，ADH基因的分子表征主要是在 cDNA水平，仅ADH2基因座的基因组结构才是 阐明。作为对理解遗传学的第一步 酒精敏感性，我们建议表征所有ADH基因，包括 不仅是A类ADH1，ADH2和ADH3基因座的那些 II级和III基因座。使用PI的DNA，我们已经隔离了 部分基因组克隆不仅在所有这些ADH基因中，而且是新的 以前未知的ADH基因。为了表征所有 这些ADH基因完全，我们建议使用 相同的基因组DNA，筛选它并执行DNA测序。 通过使用获得的DNA序列数据，我们计划研究DNA多态性 通过聚合酶链的方法在每个ADH基因座的信息区域 反应和直接基因组测序。这些数据和其他已发布的数据 还将用于研究ADH基因分化的模式。