Variation in alcohol pharmacokinetics as a risk factor for alcohol dependence

Background: The significant association between alcohol dehydrogenase (ADH) -2 genotype and alcohol-dependence risk, demonstrated in both Asian and non -Asian populations, suggests a link between the metabolism of alcohol (etha nol) and individual differences in susceptibility to dependence. Methods: We tested this hypothesis by following up on subjects who took par t in the Alcohol Challenge Twin Study conducted in 1979-1981 and comparing the blood and breath alcohol results in that study between subjects who sub sequently did or did not meet diagnostic criteria for lifetime alcohol depe ndence in 1992-1993. Results: Subjects who met DSM-III-R criteria for lifetime alcohol dependenc e at follow-up had higher blood and breath alcohol values after alcohol cha llenge than never-dependent subjects. Multivariate analysis showed independ ent effects of susceptibility to alcohol dependence and smoking status on b lood alcohol concentrations, whereas habitual alcohol intake at the time of the initial study had marginally significant effects. The risk of alcohol dependence was 2-fold higher in men and 3-fold higher in women with blood o r breath alcohol concentrations in the highest quartile than in the lowest quartile. Conclusions: In view of this association and the known genetic influences o n both alcohol pharmacokinetics and alcohol dependence, it is probable that part of the heritability of dependence is mediated by genes (other than th e known ADH2 and ADH3 polymorphisms) affecting alcohol metabolism.