Stress–response pathways are altered in the hippocampus of chronic alcoholics

• Published in: Alcohol (Fayetteville, N.Y.) N.Y.), 2013-11, Vol.47 (7), p.505-515
• Main Authors: McClintick, Jeanette N, Xuei, Xiaoling, Tischfield, Jay A, Goate, Alison, Foroud, Tatiana, Wetherill, Leah, Ehringer, Marissa A, Edenberg, Howard J
• Format: Article
• Language: English
• Subjects: Adult; Aged; Alcoholics; Alcoholism; Alcoholism - physiopathology; Arrays; Brain; Cortisol; Female; Gene expression; Gene Ontology; Genomics; GWAS; Hippocampus; Hippocampus - physiopathology; Humans; Hypoxia - genetics; Inflammation; Inflammation - genetics; Kinases; Male; Middle Aged; Neurodegeneration; Neurogenesis; NF-kappa B - genetics; NF-κB; Principal components analysis; Psychiatry; Stress; Studies; Transcriptome
• ISSN: 0741-8329; 1873-6823
• DOI: 10.1016/j.alcohol.2013.07.002

Abstract The chronic high-level alcohol consumption seen in alcoholism leads to dramatic effects on the hippocampus, including decreased white matter, loss of oligodendrocytes and other glial cells, and inhibition of neurogenesis. Examining gene expression in post mortem hippocampal tissue from 20 alcoholics and 19 controls allowed us to detect differentially expressed genes that may play a role in the risk for alcoholism or whose expression is modified by chronic consumption of alcohol. We identified 639 named genes whose expression significantly differed between alcoholics and controls at a False Discovery Rate (FDR) ≤ 0.20; 52% of these genes differed by at least 1.2-fold. Differentially expressed genes included the glucocorticoid receptor and the related gene FK506 binding protein 5 ( FKBP5 ), UDP glycosyltransferase 8 ( UGT8 ), urea transporter ( SLC14A1 ), zinc transporter ( SLC39A10 ), Interleukin 1 receptor type 1 ( IL1R1 ), thioredoxin interacting protein ( TXNIP ), and many metallothioneins. Pathways related to inflammation, hypoxia, and stress showed activation, and pathways that play roles in neurogenesis and myelination showed decreases. The cortisol pathway dysregulation and increased inflammation identified here are seen in other stress-related conditions such as depression and post-traumatic stress disorder and most likely play a role in addiction. Many of the detrimental effects on the hippocampus appear to be mediated through NF-κB signaling. Twenty-four of the differentially regulated genes were previously identified by genome-wide association studies of alcohol use disorders; this raises the potential interest of genes not normally associated with alcoholism, such as suppression of tumorigenicity 18 ( ST18 ), BCL2-associated athanogene 3 ( BAG3 ), and von Willebrand factor ( VWF ).