Strong protective effect of the aldehyde dehydrogenase gene (ALDH2) 504lys (*2) allele against alcoholism and alcohol-induced medical diseases in Asians

Abstract

Alcohol is oxidized to acetaldehyde, which in turn is oxidized to acetate. The aldehyde dehydrogenase 2 gene (ALDH2) is the most important gene responsible for acetaldehyde metabolism. Individuals heterozygous or homozygous for the lys (A or *2) allele at the single nucleotide polymorphism (SNP) glu504lys (rs671) of ALDH2 have greatly reduced ability to metabolize acetaldehyde, which greatly decreases their risk for alcohol dependence (AD). Case-control studies have shown association between this SNP and alcohol dependence as well as alcohol-induced liver disease. However, some studies have produced insignificant results. Using cumulative data from the past 20 years predominately from Asian populations (from both English and Chinese publications), this meta-analysis sought to examine and update whether the aggregate data provide new evidence of statistical significance for the proposed association. Our results (9,678 cases and 7,331 controls from 53 studies) support a strong association of alcohol abuse and dependence, with allelic P value of 3×10−56 and OR of 0.23 (0.2, 0.28) under the random effects model. The dominant model (lys-lys + lys-glu vs. glu-glu) also showed strong association with P value of 1×10−44 and OR of 0.22 (0.18, 0.27). When stricter criteria and various sub-group analyses were applied, the association remained strong (for example, OR = 0.23 (0.18, 0.3) and P = 2×10−28 for the alcoholic patients with alcoholic liver disease, cirrhosis, or pancreatitis). These findings provide confirmation of the involvement of the human ALDH2 gene in the pathogenesis of AD as well as alcohol-induced medical illnesses in East-Asians.

Effects of genetic variants of ADH1B and ALDH2 and social network on continued alcohol drinking among young adolescents in Taiwan

“…Nevertheless, this is not to imply that the protective effect of ADH1B*2 and ALDH2*2 on more intensive alcohol use, such as abuse or dependence that may lead to greater intensity of acetaldehyde accumulation, would diminish as well. Adults with these protective genotypes have been associated with reduced risk of alcohol use disorders (Chen et al, 1996;Hendershot et al, 2009;Li et al, 2012;Luczak et al, 2006;Takeshita and Morimoto, 1996). Intriguingly, the diminishing protection by the genetic variants in alcohol-metabolizing genes among adolescents in the face of puberty-initiated changes is in line with a previous finding about the secular trend of the decreasing protection by ALDH2*2 against developing alcohol-use disorders in Japan as a result of mounting psychosocial stresses (Higuchi et al, 1994).…”

“…After consumption of alcohol, build-up of acetaldehyde in tissues may lead to flush and several other dysphoric symptoms and hence to reduction of an individual's alcohol drinking (Chen et al, 1998). These variants of ADH1B and ALDH2, highly prevalent in Asian populations, have been associated with reduced risk of alcohol use disorders (Chen et al, 1996;Hendershot et al, 2009;Li et al, 2012;Luczak et al, 2006;Takeshita and Morimoto, 1996). Notably, in Asian populations the estimated protective effect of ALDH2*2 is much stronger than that of ADH1B*2 (Chen et al, 1996;Luczak et al, 2006).…”

Enzymatic Aspects of Alcoholism-ADH and ALDH

“…Moreover, the active form of ALDH2 was associated with hypertension. A meta-analysis of East Asian case-control studies showed the same results; that is, less-active ADH1B and active ALDH2 are associated with a high incidence of liver disease, cirrhosis, and pancreatitis (Li et al 2011(Li et al , 2012. This association might be due to differences in alcohol consumption in subjects due to variations in ADH1B and ALDH2.…”

Phenome-Wide Association Study for Alcohol and Nicotine Risk Alleles in 26394 Women

“…As both drinking and smoking behaviors are strongly associated with numerous health consequences, many studies have sought to link genes implicated in risk for smoking and drinking behaviors to the adverse health consequences of these behaviors, obtaining consistent results (Druesne-Pecollo et al, 2009;Li et al, 2011Li et al, , 2012Chen et al, 2015;Hallden et al, 2015). However, owing to the potent effects that nicotine, alcohol, and their metabolites have on the human body (Guo and Ren, 2010;Drug Therapeutics Bulletin, 2014), smoking and drinking behaviors and their associated genes (with large effects on nicotine response and acetaldehyde metabolism, respectively) might be involved in a much wider range of health conditions and human behaviors than is currently recognized.…”