These results strongly reflect the well-described effect of chronic alcohol exposure on different aspects of the innate and acquired immune systems [52]. Chronic alcohol exposure accelerates the inflammatory response and reduces anti-inflammatory cytokines [52]. An activated immune response in response to chronic alcohol exposure has been shown on the cell level [53], as well as on the transcription [53], and protein levels [54, 55]. In a previous EWAS, we found strong enrichment of immune processes in differentially methylated CpG-sites associated with alcohol withdrawal [56]. Neuroinflammation has been repeatedly associated with AUD and both the glutamate excitotoxicity and the production of acetaldehyde, key processes in AUD metabolism, have been suggested to produce an inflammatory response in the brain [57]. On a phenotypic level, there is also widespread overlap between symptoms of inflammation and of SUDs, such as anhedonia, depression, and decreased cognitive functioning [58]. In addition, in candidate gene studies in postmortem human PFC, hippocampus, and orbitofrontal cortex, increased mRNA levels of HMGB1, which encodes a proinflammatory cytokine and toll-like receptor genes have been associated with alcohol consumption in AUD cases,
