BACKGROUND AND AIMS Withdrawal is a serious and sometimes life-threatening event in alcohol-dependent individuals. It has been suggested that epigenetic processes may play a role in this context. This study aimed to identify genes and pathways involved in such processes which hint to relevant mechanisms underlying withdrawal. DESIGN Cross-sectional case-control study and longitudinal within-cases study during alcohol withdrawal and after two weeks of recovery SETTING: Addiction medicine departments in two university hospitals in southern Germany. PARTICIPANTS/CASES Ninety-nine alcohol-dependent male patients receiving inpatient treatment and suffering from severe withdrawal symptoms during detoxification and 95 age-matched male controls. MEASUREMENTS Epigenome-wide methylation patterns in patients during acute alcohol withdrawal and after two weeks of recovery, as well as in age-matched controls using Illumina EPIC bead chips. Methylation levels of patients and controls were tested for association with withdrawal status. Tests were adjusted for technical and batch effects, age, smoking, and cell type distribution. Single site analysis as well as an analysis of differentially methylated regions, and gene ontology analysis were performed. FINDINGS We found pronounced epigenome-wide significant (false discovery rate [FDR]<0.05) differences between patients during withdrawal and after two weeks (2,876 CpG sites), as well as between patients and controls (9,845 and 6,094 CpG sites comparing patients at time point 1 and patients at time point 2 versus controls, respectively). Analysis of differentially methylated regions and involved pathways revealed an overrepresentation of gene ontology terms related to the immune system response. Differences between patients and controls diminished after recovery (>800 CpG sites less), suggesting a partial reversibility of alcohol- and withdrawal-related methylation. CONCLUSIONS Acute alcohol withdrawal in severely dependent male patients appears to be associated with extensive changes in epigenome-wide methylation patterns. In particular, genes involved in immune system response seem to be affected by this condition.

中文翻译：

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男性急性酒精戒断和恢复导致 DNA 甲基化谱发生深刻变化——一项纵向临床研究

背景和目的戒断是酒精依赖个体的严重且有时危及生命的事件。有人提出表观遗传过程可能在这种情况下发挥作用。这项研究旨在确定参与这些过程的基因和途径，这些基因和途径暗示了戒断的相关机制。设计 酒精戒断期间和恢复两周后的横断面病例对照研究和纵向病例内研究 设置：德国南部两家大学医院的成瘾医学科。参与者/案例 99 名酒精依赖男性患者接受住院治疗并在戒毒期间出现严重的戒断症状，​​以及 95 名年龄匹配的男性对照组。测量 患者在急性酒精戒断期间和恢复两周后的表观基因组范围的甲基化模式，以及使用 Illumina EPIC 珠芯片的年龄匹配对照。测试患者和对照的甲基化水平与戒断状态的关联。测试针对技术和批次效应、年龄、吸烟和细胞类型分布进行了调整。进行了单位点分析以及差异甲基化区域的分析和基因本体分析。结果 我们发现停药期间和两周后患者之间以及患者和对照之间（9,845 和 6,094 个 CpG 位点比较患者的时间）之间存在明显的表观基因组范围的显着差异（错误发现率 [FDR]<0.05）点 1 和时间点 2 的患者与对照组相比）。差异甲基化区域和相关通路的分析揭示了与免疫系统反应相关的基因本体术语的过度表达。恢复后患者和对照组之间的差异减少（> 800 个 CpG 位点减少），表明酒精和戒断相关甲基化的部分可逆性。结论 严重依赖男性患者的急性酒精戒断似乎与表观基因组范围甲基化模式的广泛变化有关。特别是，参与免疫系统反应的基因似乎受到这种情况的影响。表明酒精和戒断相关甲基化的部分可逆性。结论 严重依赖男性患者的急性酒精戒断似乎与表观基因组范围甲基化模式的广泛变化有关。特别是，参与免疫系统反应的基因似乎受到这种情况的影响。表明酒精和戒断相关甲基化的部分可逆性。结论 严重依赖男性患者的急性酒精戒断似乎与表观基因组范围甲基化模式的广泛变化有关。特别是，参与免疫系统反应的基因似乎受到这种情况的影响。