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

Masako Yokoyama,Akira Yokoyama,Mitsuru Kimura,Tetsuji Yokoyama,Nadine Bernhardt,Sachio Matsushita

doi:10.1371/journal.pone.0255276

Masako Yokoyama, Akira Yokoyama + Show 4 more

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https://doi.org/10.1371/journal.pone.0255276

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Abstract

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. 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. 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. 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.

Highlights

Alcohol dehydrogenases (ADHs) oxidize ethanol to acetaldehyde, and aldehyde dehydrogenases (ALDHs) oxidize acetaldehyde to acetate
Alcohol flushing is influenced by the ALDH2 and ADH1B genotypes, constitutional or acquired flushing tolerance is an independent susceptibility trait for alcohol dependence (AD)
The inactive ALDH2 2 allele, which results in slow acetaldehyde elimination, and the fast-metabolizing ADH1B 2 allele, which results in fast acetaldehyde production, both enhance alcohol-induced facial flushing [1,2,3,4,5,6] and are strong Asian protective factors against alcohol dependence [7,8,9,10]

Summary

Introduction

Alcohol dehydrogenases (ADHs) oxidize ethanol to acetaldehyde, and aldehyde dehydrogenases (ALDHs) oxidize acetaldehyde to acetate. The inactive ALDH2 2 allele (rs671), which results in slow acetaldehyde elimination, and the fast-metabolizing ADH1B 2 allele (rs1229984), which results in fast acetaldehyde production, both enhance alcohol-induced facial flushing [1,2,3,4,5,6] and are strong Asian protective factors against alcohol dependence [7,8,9,10]. ALDH2 plus ADH1B genotyping using buccal smear DNA is commercially available and inexpensive in Japan. Knowing an individual’s own ALDH2 plus ADH1B genotype is a growing preventive strategy against alcohol dependence. The combination of the alcohol flushing status and ALDH2 plus ADH1B genotype may have a better performance for predicting the alcohol-dependence risk in comparison with alcohol flushing alone or genotyping alone

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