Polymorphism and addiction to alcohol.

Abstract

Several lines of evidence support the hypothesis that alcoholism has a heritable component. These include studies in monozygotic and dizygotic twins, family studies and studies in adopted individuals where alcohol use has been documented in biological and adopting parents. Such studies estimate the heritable component at 50–60%. One important aspect of susceptibility to alcoholism involves inherited variation (polymorphism) in genes which influence alcohol metabolism. The major pathway for alcohol metabolism is shown in Figure 1. Central to an understanding of this area are the aversive effects of higher levels of acetaldehyde with lower intakes of alcohol. High levels of acetaldehyde often result in facial flushing, tachycardia, nausea and vomiting. The polymorphism with the greatest effect on acetaldehyde levels is that associated with aldehyde dehydrogenase 2 (ALDH2). The normal allele is called ALDH2*1 while the mutant allele (ALDH2*2) is associated with ALDH2 deficiency in both heterozygotes and homozygotes. Metabolism of ethanol is influenced by polymorphism in alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH). Polymorphisms that promote higher levels of acetaldehyde with lower intakes of alcohol are associated with lower risks for alcoholism. Individuals with the ALDH2*2 allele are rare in Caucasian populations but the frequency among Japanese, Chinese and Koreans (heterozygous and homozygous) ranges from 30 to 50%. This has important effects on risk for alcoholism because alcoholism is virtually unknown in homozygotes for ALDH2*2, whereas heterozygotes show a 5–10-fold reduction in risk. Other polymorphisms with potential effects on acetaldehyde levels include various alcohol dehydrogenases (ADH) and the cytochrome P450 enzyme (CYP2E1). Of the seven ADH genes in humans, ADH2 and ADH3 are known to be polymorphic with three and two alleles, respectively. Alleles associated with somewhat higher ADH activity (ADH2*2 and ADH3*1) may enhance the aversive effects of alcohol, while those with slower activity (ADH2*1 and ADH3*2) may increase alcohol tolerance and promote alcoholism. These hypotheses are supported by some studies but, overall, the effect of ADH genotype on alcohol metabolism is relatively small. Levels of CYP2E1 can be influenced by both genetic polymorphism and high intakes of alcohol but promoter variants of CYP2E1 do not appear to affect drinking behavior. Another area that might be influenced by genetic polymorphism is the neurobiology of addiction. Some authors have viewed alcoholism as a reward deficiency syndrome that might be influenced by variation in the effects of a variety of neurotransmitters such as serotonin, dopamine, gamma aminobutyric acid, glutamate and β endorphin. This hypothesis is supported by an apparent reduction in addictive behavior with the use of drugs such as naltrexone and acamposate. Although several polymorphisms have been described in neurotransmitter receptor, promoter and transporter genes, there is, as yet, no clear association with addiction to alcohol or other drugs. The final consideration is that of genetic effects on sensitivity to alcohol. With a standard alcohol challenge, features such as subjective intoxication and results from tests of coordination vary widely between individuals. Those who are highly sensitive have a low risk for alcoholism while the reverse applies to those who appear to be highly tolerant (low sensitivity). Twin studies indicate that alcohol sensitivity has an important heritable component but whether this has a biological basis related to polymorphisms in neurotransmitter genes or stress response genes remains unclear. Agarwal DP. Pathol. Biol. 2001; 49: 703–9. Weiss F et al. J. Neurosci. 2002; 22: 3332–37. Enoch M-A. Am. J. Pharmacogenomics 2003; 3: 217–32.