The Alcohol Flushing Response is Associated with the Risk of Depression

The alcohol flushing response is experienced by 36–45% of East Asians after drinking a small amount of alcohol. Since individuals with this response are incapable of metabolizing toxic acetaldehyde derived from alcohol effectively, this response is suggested as an indicator for the health risks associated with alcohol intake. Depression, a major health problem linked to alcohol consumption, might also be associated with the presence of the alcohol flushing response. Therefore, this study examined the association between the alcohol flushing response and the risk of depression in the general population of South Koreans. The analysis included 139,266 participants and used data from the 2019 Korean Community Health Survey. Only current drinkers were considered in the analysis. The relationship between the alcohol flushing response and depression was determined by logistic regression analysis using SAS 9.4. As a result, more than one-third of the population was found to be current flushers, and the relationship was significant among current flushers and depression (AOR=1.23, 95% CI 1.12–1.35, P-value=0.1ⅹ10-3) compared to never flushers. No association was found between former flushing response and depression. The odds of depression were significantly higher among alcohol flushers who drinks less than 15 g/day alcohol (<5 g/day: AOR=1.21, 95% CI=1.08-1.36, P-value=0.1ⅹ10-3; 5.0-14.9 g/day: AOR=1.40, 95% CI=1.14-1.71, P-value=0.1ⅹ10-3). In conclusion, this study reveals that a significant number of the South Korean population experiences the alcohol flushing response, and the individuals with the response are more likely to feel depressed, even with a small amount of alcohol consumption.

Alcohol Consumption and Cigarette Smoking among Young Adults: An Instrumental Variable Analysis Using Alcohol Flushing

Association between drinking and smoking has remained controversial since the association between two studies were influenced by various confounding. Thus, our study aimed to explore the causal effect of alcohol consumption and cigarette smoking using alcohol flushing as an instrument variable, which is free from confounders. We analyzed cross-sectional survey data from 2500 Korean young adults (1600 men and 900 women). Alcohol flushing was strongly associated with log transformed alcohol consumption (F = 272). In men, alcohol non-flushers were 1.41 times (95% CI 1.28–1.55) more likely to smoke 100 cigarettes in their lifetime in logistic regression analysis. Alcohol non-flushers were also 1.3 times (95% CI 1.21–1.40) more likely to become daily smokers and 1.39 times (95% CI 1.27–1.51) more likely to be current smokers than alcohol flushers. However, in an IV analysis, no causal relationships between alcohol consumption and smoking status were found. Alcohol consumption, on the other hand, was causally associated with lowering nicotine dependence and former smoking in men. Alcohol consumption determined by alcohol flushing status does not appear to be causally linked to the smoking behavior of young adults. The relationship between alcohol consumption and nicotine dependence and smoking cessation needs further study.

Combinations of alcohol-induced flushing with genetic polymorphisms of alcohol and aldehyde dehydrogenases and the risk of alcohol dependence in Japanese men and women

Objective The risk of alcohol dependence (AD) in Japanese men and women was evaluated according to combinations of alcohol flushing and aldehyde dehydrogenase-2 (ALDH2, rs671) and alcohol dehydrogenase-1B (ADH1B, rs1229984) genotypes, all of which are known to determine AD susceptibility in Asians. Previous studies have focused on men, since women account for a smaller proportion of AD subjects. Methods Case control studies were conducted between 3721 male and 335 female AD Japanese and 610 male and 406 female controls who were asked about their current or former tendency to experience facial flushing after drinking a glass of beer and underwent ALDH2 and ADH1B genotyping. The time at which alcohol-induced facial flushing tendencies had disappeared in former-flushing AD subjects was also evaluated. Results Current alcohol flushing, the inactive ALDH2*1/*2 genotype, and the fast-metabolizing ADH1B*2 allele were less frequently found in the AD groups. Although alcohol flushing was strongly influenced by the ALDH2 and ADH1B genotypes, multiple logistic model showed that never or former flushing and the genotype combinations were independent strong risk factors of AD in men and women. Never or former flushing (vs. current flushing) markedly increased the odds ratios of AD in carriers of each of the ALDH2 and ADH1B genotype combinations. The temporal profiles for drinking and flushing in former-flushing AD subjects revealed that the flushing response disappeared soon after or before the start of habitual drinking during young adulthood, regardless of the ALDH2 genotype. Conclusion Although alcohol flushing is influenced by the ALDH2 and ADH1B genotypes, constitutional or acquired flushing tolerance is an independent susceptibility trait for AD. The combination of the alcohol flushing status and the ALDH2 and ADH1B genotypes can provide a better new strategy for AD risk assessment than the alcohol flushing status alone or the genotypes alone in Asian men and women.

Digenic mutations in ALDH2 and ADH5 impair formaldehyde clearance and cause a multisystem disorder, AMeD syndrome

Rs671 in the aldehyde dehydrogenase 2 gene (ALDH2) is the cause of Asian alcohol flushing response after drinking. ALDH2 detoxifies endogenous aldehydes, which are the major source of DNA damage repaired by the Fanconi anemia pathway. Here, we show that the rs671 defective allele in combination with mutations in the alcohol dehydrogenase 5 gene, which encodes formaldehyde dehydrogenase (ADH5FDH), causes a previously unidentified disorder, AMeD (aplastic anemia, mental retardation, and dwarfism) syndrome. Cellular studies revealed that a decrease in the formaldehyde tolerance underlies a loss of differentiation and proliferation capacity of hematopoietic stem cells. Moreover, Adh5−/−Aldh2E506K/E506K double-deficient mice recapitulated key clinical features of AMeDS, showing short life span, dwarfism, and hematopoietic failure. Collectively, our results suggest that the combined deficiency of formaldehyde clearance mechanisms leads to the complex clinical features due to overload of formaldehyde-induced DNA damage, thereby saturation of DNA repair processes.