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Aims: Wernicke-Korsakoff syndrome (WKS) is commonly associated with chronic alcohol misuse, a condition known to have multiple detrimental effects on thiamine metabolism. This study was conducted to identify genetic variants that may contribute to the development of WKS in individuals with alcohol dependence syndrome through alteration of thiamine transport into cells., Methods: Exome sequencing data from a panel of genes related to alcohol metabolism and thiamine pathways were analysed in a discovery cohort of 29 individuals with WKS to identify possible genetic risk variants associated with its development. Variant frequencies in this discovery cohort were compared with European frequencies in the Genome Aggregation Database browser, and those present at significantly higher frequencies were genotyped in an additional cohort of 87 alcohol-dependent cases with WKS and 197 alcohol-dependent cognitively intact controls., Results: Thirty non-synonymous variants were identified in the discovery cohort and, after filtering, 23 were taken forward and genotyped in the case-control cohort. Of these SLC19A1:rs1051266:G was nominally associated with WKS. SLC19A1 encodes the reduced folate carrier, a major transporter for physiological folate in plasma; rs1051266 is reported to impact folate transport. Thiamine pyrophosphate (TPP) efflux was significantly decreased in HEK293 cells, stably transfected with rs1051266:G, under thiamine deficient conditions when compared with the efflux from cells transfected with rs1051266:A (P = 5.7 × 10-11)., Conclusion: This study provides evidence for the role of genetic variation in the SLC19A1 gene, which may contribute to the development of WKS in vivo through modulation of TPP transport in cells., (© The Author(s) 2022. Medical Council on Alcohol and Oxford University Press. All rights reserved.)

Heavy drinking leads to premature aging and precipitates the onset of age-related diseases. Acetaldehyde (AcH), a toxic metabolite of ethanol, has been implicated in various types of cancer. However, whether alcohol accelerates biological aging at a cellular level is controversial and the mechanism involved is unclear. We addressed these questions by measuring telomere length (TL) in peripheral blood leukocytes of Japanese patients with alcohol dependence (AD) and examined the association between TL, genetic variants of alcohol dehydrogenase (ADH)1B and aldehyde dehydrogenase (ALDH)2, and other clinical characteristics. A total of 134 male AD patients and 121 age- and sex-matched healthy controls were evaluated. All patients received endoscopic screening for cancer of the upper aerodigestive tract (UADT). TL was almost 50% shorter in AD patients relative to controls. There were no significant differences in TL between AD patients with and without UADT cancer, and no associations between ADH1B and ALDH2 genotypes and TL. AD patients with thiamine (vitamin B1) deficiency at admission had significantly shorter TL than those with normal thiamine status. Although the exact mechanism underlying the shorter TL in AD patients remain unclear, our findings suggest that alcohol rather than AcH is associated with telomere shortening in AD, which may be accelerated by thiamine deficiency. Future studies should also focus on the association between telomere shortening and TD in the context of oxidative stress., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Chronic alcohol consumption results in structural changes to the brain. In alcoholics without coexisting thiamine deficiency or liver disease this is largely restricted to a loss of white-matter volume. When it occurs, neuronal loss is limited in anatomic distribution and only detected with quantitative techniques. This relative paucity of neurodegeneration is reflected in studies of gene and protein expression in postmortem brain where findings are subtle and discordant between studies. In alcoholics with coexisting pathologies, neuronal loss is more marked and affects a wider range of anatomic regions, especially subcortical nuclei. Although this more widespread damage may reflect a more severe drinking history, there is evidence linking thiamine deficiency and the consequences of liver disease to the pathogenesis of alcohol-related brain damage. Furthermore, a range of other factors, such as cigarette smoking and mood disorders, that are common in alcoholics, have the potential to influence studies of brain pathology and should be considered in further studies of the neuropathology of alcoholism., (© 2014 Elsevier B.V. All rights reserved.)

Thiamine deficiency has been specifically linked to the development of Wernicke-Korsakoff syndrome (WK)--a degenerative brain disorder that is typically associated with alcoholic drinking. Alcoholism-related thiamine deficiency is a major cause of WK. However, an inherited abnormality in thiamine utilization has been identified in some WK patients that may predispose heavy drinkers to this severe neurological syndrome. Individuals who possess this variant require more thiamine throughout their lives to prevent them from experiencing thiamine deficiency. Recent prospective studies have implicated early childhood nutritional and environmental influences in the etiology of alcoholism in adults. These studies have suggested that developmental abnormalities involving brain white matter growth might precipitate the later development of alcoholism possibly by altering the emerging reward-related brain systems. Brain white matter growth is highly sensitive to nutritional deficiency (including thiamine deficiency) and oxidative injury, especially during the perinatal period. The proposed model of familial alcoholism hypothesizes that an inherited insensitivity to thiamine can precipitate brain abnormalities very early in life that will greatly increase the risk of developing alcoholism in adulthood. This paper offers a heuristic model of a possible mechanism by which both inherited and environmental factors related to thiamine utilization might coaggregate to cause alcoholism.

It was found that the activity of the marker thiamine-dependent enzyme, transketolase (TK), was decreased (down to 61-79% of control) in blood, liver and brain of inbred rats following a 6-month consumption of 15% ethanol as their only source of drinking fluid. After ethanol withdrawal, the enzyme activity was gradually restored, but did not reach the control values until 1 month following cessation of alcohol consumption. Moreover, in rats preferring ethanol, the decrease of TK activity was more pronounced than in water-preferring rats. Another experiment showed that thiamine deficiency induced by the thiamine antagonist, oxythiamine (200 mg/kg), led to a prolonged increase of the preferential intake of ethanol solutions in inbred rats. Significantly lower liver TK activities and thiamine pyrophosphate content were found in Finnish AA line rats as opposed to ANA line rats which had been obtained by selective outbreeding for high and low voluntary alcohol intake, respectively. Significantly lower TK activity was also found in the whole brain (89%), cerebellum (79%) and pons-medulla oblongata (87%) of AA rats as compared to ANA animals. Our own findings and the literature data confirm the hypothesis that thiamine deficiency can be both predisposing to and a consequence of, increased alcohol consumption.