Alcohol dependence and associated disease: determinants, pathogenesis and treatment

酒精是许多社会使用的一种药剂，但使用的背景可能有很大的不同。由于酒精的毒性，其负面影响可能从中毒到酒精依赖和酒精相关疾病。据估计，仅在英国，与这些后果相关的成本每年就达210亿英镑。此外，酒精对65岁以下的人的影响不成比例，世界卫生组织认为酒精是非传染性疾病的第三大原因。 除了社会和生产力的后果，酒精还涉及许多疾病状态的发展和进展。为该奖学金提出的工作将侧重于酒精依赖本身以及酒精在肝脏疾病和脑损伤中的后果。现将这些领域的工作概述如下。 酒精依赖/消费：该项目将使用定量分析来探索英国生物银行收集的遗传变异和生物测量结果，以及它们与a）酒精消费状况（滴酒不沾vs.重度饮酒）和B）酒精消费作为连续变量的关系。我们将尝试在其他国家/国际生物库中复制研究结果，或作为与从类似人群中收集样本的其他团体合作工作的一部分。在试图复制研究结果的同时，将使用模式生物使用计算和实验室技术进一步研究任何已识别的基因。这项工作的最终目的是了解英国生物银行工作发现的真正价值。希望这项工作将导致识别一个或几个标记，可用于开发新的抗酒精渴望治疗在未来。此外，英国生物银行的纵向随访将用于评估饮酒与后期疾病发展和进展以及死亡（原因）之间的关联。 酒精相关的肝脏疾病：肝脏疾病在酒精使用障碍的人群中很常见。然而，并不是所有酗酒的人都会患上与酒精有关的肝病。该项目旨在确定疾病发作/进展的早期标志物。英国生物银行将是第一个使用的数据源。这项工作的初始阶段将是使用初级和二级保健的电子健康记录来确认酒精相关肝病的诊断。然后，将使用有关个人的遗传，非遗传和肝脏扫描信息来探索确诊患者中发现的共同因素。随后将在实验室环境中使用来自GenomALC（http：//www.genomalc.org/;命名为Fellow，该联盟成员）的实验室模型和/或生物样本尝试复制任何发现。 酒精性脑损伤：酒精相关性脑损伤（ARBI）是大量饮酒引起的许多神经精神疾病的总称。在目前的医疗保健系统中，它被发现和治疗不足，但它对患者的影响以及他们坚持治疗方案的能力开始受到重视。该项目将使用英国生物银行的大脑扫描数据来描述大量饮酒对大脑结构和功能的影响。将遗传和成像数据联系起来将使酒精依赖/消费工作中识别的基因与不同大脑结构之间的关联得以探索。该项目的目的是创建酒精相关脑损伤的计算和/或实验室模型。未来的目标是与临床同事合作开发ARBI的治疗干预措施。

Alcohol is an agent used in many societies, but the context of use can greatly differ. Due to the toxic properties of alcohol, the negative effects can vary from intoxication to alcohol dependence and alcohol-related disease. The cost associated with these consequences is estimated to be £21 billion per annum in the UK alone. Moreover, alcohol disproportionately influences those under the age of 65, and is considered the third leading cause of non-communicable disease by the World Health Organisation. Alongside social and productivity consequences, alcohol is implicated in the development and progression of many disease states. The work proposed for this Fellowship will focus on alcohol dependence itself and alcohol's consequences in the setting of liver disease and brain injury. The work in each of these areas is summarised below. Alcohol dependence/consumption: This project will use quantitative analysis to explore genetic variants and biological measurements collected by UK Biobank and their association with a) alcohol consumption status (teetotal vs. very heavy drinking), and b) alcohol consumption as a continuous variable. We will attempt to replicate findings in other national/international Biobanks or as part of collaborative work with other groups that have collected samples from similar people. At the same time as attempting to replicate findings, any identified genes will be further investigated using both computational and laboratory techniques using model organisms. The ultimate aim of this work is to understand the true value of the findings from the UK Biobank work. It is hoped that this work will lead to the identification of one or several markers that can be used to develop new anti-craving treatments for alcohol in the future. Furthermore, longitudinal follow-up in UK Biobank will be used to assess association between alcohol consumption and later disease development and progression and (cause of) death. Alcohol-related liver disease: Liver disease is common in people that have alcohol use disorders. However, not all people that drink heavily develop alcohol-related liver disease. This project within the fellowship aims to identify early markers of disease onset/progression. UK Biobank will be the first data source to be used. The initial stages of this work will be to confirm the diagnosis of alcohol-related liver disease using electronic health records from primary and secondary care. The genetic, non-genetic and liver scan information available about the individuals will then be used to explore common factors found in those with a confirmed diagnosis. Subsequent replication of any findings will then be attempted in a laboratory setting using laboratory models and/or biological samples from GenomALC (http://www.genomalc.org/; named Fellow a member of the Consortium). Alcohol-related brain injury: Alcohol Related Brain Injury (ARBI) is an umbrella term for a number of neuropsychiatric conditions caused by heavy drinking. It is under-detected and under-treated in current healthcare systems, but its impact on the patient and their ability to adhere to treatment packages is beginning to be appreciated. This project will use UK Biobank brain scan data to delineate the consequences of heavy alcohol consumption on brain structure and function. Linking genetic and imaging data will enable the association between genes identified in the alcohol dependence/consumption work and different brain structures to be explored. The aim of this project is to create computational and/or laboratory models of alcohol-related brain injury. It would then be a future aim to work with clinical colleagues to develop therapeutic interventions for ARBI.