Impaired Regulation of ALDH2 Protein Expression Revealing a Yet Unknown Epigenetic Impact of rs886205 on Specific Methylation of a Negative Regulatory Promoter Region in Alcohol-Dependent Patients

Abstract

Acetaldehyde, the carcinogenic metabolite of ethanol known to provoke aversive symptoms of alcohol consumption, is predominantly eliminated by aldehyde dehydrogenase 2 (ALDH2). Reduced ALDH2 activity correlates with low alcohol tolerance and low risk for alcohol dependence. The ALDH2 promoter polymorphism rs886205 (A>G) is associated with decreased promoter activity, but a molecular mechanism and allele-dependent ALDH2 protein expression has not been described yet. On the basis of allele-dependent epigenetic effects, we analyzed the rs886205 genotype, methylation rates of cytosine-phosphatidyl-guanine (CpG)-sites within a regulatory promoter region and ALDH2 protein levels in 82 alcohol-dependent patients during a 2-week withdrawal and compared them to 34 matched controls. Patients without the G-allele of rs886205 showed higher methylation of the promoter region than controls and readily adapted epigenetically as well as on protein level during withdrawal, while patients with the G-allele displayed retarded methylation readjustment and no change in ALDH2 protein levels. Our data provide novel insights into an unknown genetic-epigenetic interaction, revealing impaired ALDH2 protein expression in patients with the G-allele of rs886205. Additionally, we checked for an association between rs886205 and protection against alcohol dependence and found a trend association between the G-allele and protection against alcohol dependence that needs replication in a larger Caucasian cohort.

Genetic polymorphisms inALDH2are associated with drug addiction in a Chinese Han population

“…Furthermore, one recent study has reported that rs886205 is associated with altered methylation levels of the negative regulatory promoter fragment and corresponding ALDH2 protein levels in alcohol-dependent patients’ blood during withdrawal [14]. Our data shown that rs886205 is associated with a decreased risk of drug addiction.…”

Genetics and Epigenetics of Aldehyde Dehydrogenase (ALDH2) in Alcohol Related Liver Disease

“…This kind of interaction between ALDH2 genetic variants and DNA methylation has also been previously described in two studies in individuals with AUD. These studies investigated the influence of the ALDH2 promoter polymorphism rs886205 on DNA methylation and found that DNA methylation levels differed between those with A and G alleles and that methylation changes during the course of alcohol withdrawal were also distinct (Haschemi Nassab et al, 2016;Pathak et al, 2017). While our sample size for this type of analysis was small, it highlights the importance of looking into genetic influences on DNA methylation.…”

Changes in DNA methylation persist over time in males with severe alcohol use disorder—A longitudinal follow‐up study

“…Similarly, in ALDH2 , the promoter region is regulated by the nuclear receptor superfamily binding to the nuclear receptor response element, upstream to the transcription start site (Pathak et al, 2017; Stewart et al, 1998). Polymorphisms in the promoter elements are known to influence DNA methylation, which might affect the mRNA levels of ALDH2 after alcohol consumption (Haschemi Nassab et al, 2016; Nishimura, Kimura, Abe, Fukunaga, & Saijoh, 2006; Pathak et al, 2017).…”

“…Previously, CpG sites upstream of the ALDH2 gene have been reported to have significantly higher methylation in subjects with alcohol dependence (Haschemi Nassab et al, 2016;Pathak et al, 2017). However, methylation of MTHFR gene remains unexplored in humans in the background of AUD.…”