INHERITED SUSCEPTABILITY TO ALCOHOLISM

遗传性酗酒

• 批准号: 6371442
• 负责人: PAUL MANOWITZ
• 金额: $ 34.97万
• 依托单位: UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-08-01 至 2003-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6371442
• 关键词: African American; alcohol dehydrogenase; alcoholic beverage consumption; clinical research; congenital disorders; cytochrome P450; embryo /fetus toxicology; enzyme activity; ethanol; female; fetal alcohol syndrome; gel mobility shift assay; gene environment interaction; gene expression; gene frequency; genetic polymorphism; genetic susceptibility; human genetic material tag; human pregnant subject; protein isoforms; racial /ethnic difference; restriction fragment length polymorphism; toxin metabolism; transcription factor; African American; alcohol dehydrogenase; alcoholic beverage consumption; clinical research; congenital disorders; cytochrome P450; embryo /fetus toxicology; enzyme activity; ethanol; female; fetal alcohol syndrome; gel mobility shift assay; gene environment interaction; gene expression; gene frequency; genetic polymorphism; genetic susceptibility; human genetic material tag; human pregnant subject; protein isoforms; racial /ethnic difference; restriction fragment length polymorphism; toxin metabolism; transcription factor

The role of genetic factors in alcoholism is well-established. Like most common diseases, it is likely that mutations at several or many different loci predispose to alcoholism. One mutation that may predispose to alcoholism is a mutation at nucleotide 1788 of the arylsulfatase A locus. A consequence of the amino acid alteration due to this mutation is that the enzyme lacks an oligosaccharide moiety and is metabolically labile in the cell. The arylsulfatase A activity is reduced in cells homozygous for this mutation. Alcoholic patients have an excess of homozygotes with this mutation compared with the prevalence observed in nonalcoholic populations. Acceptance of these previous findings has been limited by the fact that all population studies of genotype and disease frequency are vulnerable to undetected stratification. Confounders such as ethnic origins and social class can affect both the exposure (genotype) and the outcome (disease). This proposal is designed to study arylsulfatase A and other candidate genes for a possible relationship to alcoholism and behavioral/neuropsychological deficits without the influence of stratification confounders. The major hypothesis that candidate gene mutations are predisposing to alcoholism will be tested by comparing the frequency of such mutations or homozygosity for such mutations among patients with alcohol dependence to that in their sibs. A secondary goal of this research is to examine the relationship between the mutations and behavioral/neuropsychological deficits, particularly behavioral undercontrol and executive dysfunction.

遗传因素在酒精中毒中的作用是良好的。像大多数常见的疾病一样，几种或多种不同基因座的突变易于酒精中毒。 一种可能易患酒精中毒的突变是在芳基硫酸酯酶A基因座的核苷酸1788的突变。 由于这种突变引起的氨基酸改变的结果是该酶缺乏寡糖部分，并且在细胞中代谢不稳定。该突变纯合细胞中的芳基硫酸蛋白酶A活性降低。 与非酒精饮料中观察到的患病率相比，酒精患者的纯合子过量过量。 接受这些先前发现的接受受到了以下事实的限制：所有基因型和疾病频率的人口研究都容易受到未检测到的分层。 种族起源和社会阶层等混杂因素会影响暴露（基因型）和结果（疾病）。 该建议旨在研究芳基硫酸蛋白酶A和其他候选基因，以与酒精中毒和行为/神经心理学缺陷有可能的关系，而没有分层混杂因素的影响。 候选基因突变易于酗酒的主要假设将通过比较酒精依赖患者中这种突变的频率或纯合性的频率与其SIBS中的这种突变的频率。 这项研究的次要目标是检查突变与行为/神经心理学缺陷之间的关系，尤其是行为范围内的控制和执行功能障碍。