Alcohol use disorder (AUD) is a common and chronic disorder with substantial effects on personal and public health. The underlying pathophysiology is poorly understood but strong evidence suggests significant roles of both genetic and epigenetic components. Given that alcohol affects many organ systems, we performed a cross-tissue and cross-phenotypic analysis of genome-wide methylomic variation in AUD using samples from 3 discovery, 4 replication, and 2 translational cohorts. We identified a differentially methylated region in the promoter of the proprotein convertase subtilisin/kexin 9 (PCSK9) gene that was associated with disease phenotypes. Biological validation showed that PCSK9 promoter methylation is conserved across tissues and positively correlated with expression. Replication in AUD datasets confirmed PCSK9 hypomethylation and a translational mouse model of AUD showed that alcohol exposure leads to PCSK9 downregulation. PCSK9 is primarily expressed in the liver and regulates low-density lipoprotein cholesterol (LDL-C). Our finding of alcohol-induced epigenetic regulation of PCSK9 represents one of the underlying mechanisms between the well-known effects of alcohol on lipid metabolism and cardiovascular risk, with light alcohol use generally being protective while chronic heavy use has detrimental health outcomes.

中文翻译：

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甲基化分析和复制表明 PCSK9 在酒精使用障碍中的失调。

酒精使用障碍 (AUD) 是一种常见的慢性疾病，对个人和公共健康有重大影响。潜在的病理生理学知之甚少，但强有力的证据表明遗传和表观遗传成分的重要作用。鉴于酒精影响许多器官系统，我们使用来自 3 个发现、4 个复制和 2 个翻译队列的样本对 AUD 中的全基因组甲基组变异进行了跨组织和跨表型分析。我们在与疾病表型相关的前蛋白转化酶枯草杆菌蛋白酶/kexin 9 (PCSK9) 基因的启动子中发现了一个差异甲基化区域。生物学验证表明，PCSK9 启动子甲基化在组织中是保守的，并且与表达呈正相关。AUD 数据集中的复制证实了 PCSK9 低甲基化，AUD 的翻译小鼠模型显示酒精暴露导致 PCSK9 下调。PCSK9 主要在肝脏中表达并调节低密度脂蛋白胆固醇 (LDL-C)。我们对酒精诱导的 PCSK9 表观遗传调控的发现代表了众所周知的酒精对脂质代谢和心血管风险的影响之间的潜在机制之一，轻度饮酒通常具有保护作用，而长期大量饮酒则对健康有害。