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

ObjectiveThe risk of alcohol dependence (AD) in Japanese men and women was evaluated according to combinations of alcohol flushing andaldehyde dehydrogenase-2(ALDH2, rs671) andalcohol 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.MethodsCase 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 underwentALDH2andADH1Bgenotyping. The time at which alcohol-induced facial flushing tendencies had disappeared in former-flushing AD subjects was also evaluated.ResultsCurrent alcohol flushing, the inactiveALDH2*1/*2genotype, and the fast-metabolizingADH1B*2allele were less frequently found in the AD groups. Although alcohol flushing was strongly influenced by theALDH2andADH1Bgenotypes, 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 theALDH2andADH1Bgenotype 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 theALDH2genotype.ConclusionAlthough alcohol flushing is influenced by theALDH2andADH1Bgenotypes, constitutional or acquired flushing tolerance is an independent susceptibility trait for AD. The combination of the alcohol flushing status and theALDH2andADH1Bgenotypes 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.