Investigating a 'protective gene' against alcoholism

December 16, 2001

Many alcohol researchers believe that a person's genetic predisposition interacts with their environment to produce his or her overall risk for alcoholism. In addition, ethnic differences in rates of alcohol use and abuse have been linked to differences in the genes that code for certain enzymes that break down alcohol.

Two enzymes in particular - alcohol dehydrogenase (ADH) and mitochondrial aldehyde dehydrogenase (ALDH) - are highly involved in alcohol metabolism. The ADH2*3 allele (a variation of the gene) has been documented to occur only in persons of African descent and certain Native American tribes. A study in the December issue of Alcoholism: Clinical & Experimental Research investigates if an association exists between the presence of ADH2*3 alleles in young African American adults and a family history of alcohol dependence.

"We know that alcoholism is hereditary," said Cindy L. Ehlers, associate professor of neuropharmacology at The Scripps Research Institute and lead author of the study. "But we only have very limited information on what is inherited, and almost no information on what genes might be involved except in the case of alcohol metabolizing enzymes."

Differences in alcohol metabolizing enzymes, and the genes that encode them, are the best understood factors that influence drinking behavior and the risk of alcoholism. Alcohol is metabolized principally in the liver by two enzymes that act sequentially. ADH converts alcohol to acetaldehyde, aldehyde dehydrogenase (ALDH) subsequently converts acetaldehyde to acetate. Acetate is then metabolized by tissues outside of the liver. Individuals with a mutation in the gene that encodes for ALDH2 (predominantly of Far East Asian descent) instead accumulate acetaldehyde in the blood and tissues after drinking. These individuals experience a more intense response to drinking alcohol, notably facial flushing, headaches, palpitations, dizziness and nausea. Understandably, few individuals in the world who possess two defective ALDH2 alleles (thereby intensifying their response to alcohol) have developed alcoholism.

"The present study extends previous research to the ADH2*3 allele," said Ehlers. "This gene codes for a form of the ADH enzyme which may provide more efficient or more rapid alcohol metabolism. In the past, it has been shown that African American women with this gene are less likely to have children with birth defects due to alcohol use during pregnancy. In fact, our results demonstrate that the ADH2*3 allele is associated with a negative family history of alcoholism. These findings suggest that, in this sample of young African American adults, the ADH2*3 allele may be associated with a lowered risk for the development of alcoholism."

A positive family history of alcoholism is one of the most consistent and powerful predictors of a person's risk for developing the disorder. For example, individuals with a positive family history of alcoholism (usually a father) have a four to five times greater risk for developing alcoholism.

"Therefore," explained David W. Crabb, professor of medicine, biochemistry and molecular biology, and chair of the Department of Medicine at Indiana University Medical Center, "having a biological relative such as a father or brother who is alcoholic increases the chances of an individual developing the disease. However, as with all genetic diseases, not all offspring or relatives get the risk genes, and all individuals live in different environments that affect risk."

It is this interaction between a genetic predisposition for alcoholism and environmental variables that continues to intrigue researchers. Most believe that it is a 50/50 interaction.

"The variables that we believe are most important psychosocially," said Ehlers, "are religion, family intactness, being employed, and positive peer influences. These are called protective factors. Their opposite - that is, no religion, divorce, an absent parent or poor family ties, unemployment, and negative peer influence - are considered risk factors. These factors, like genes, can differ somewhat between ethnic groups. For instance, acculturation stress is said to influence drinking in Hispanic second-generation adolescents. Among African Americans, religion is one key variable. However, studies have shown that it is not so much practicing a religion, but rather, attending religious services that is important. And this is particularly important in supporting alcohol abstinence."

Although Crabb calls this study "long awaited," he would like to see future studies compare the presence of the high-activity ADH2*3 allele between African American alcoholics and nonalcoholics. "We would predict that the frequency of ADH2*3 will be lower in the alcoholics than in the nonalcoholics," he said. "Similar findings have been obtained with individuals with another high-activity ADH allele, ADH2*2, that is found in Asians and Jews."

"All in all," said Ehlers, "I think this finding definitely strengths the case for the genetics of alcoholism. It also further delineates the importance of ethnic and cultural differences when looking at risk and protective factors for alcoholism."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included: David A. Gilder and Lilach Harris of the Department of Neuropharmacology at The Scripps Research Institute; and Lucinda Carr of the Department of Medicine at Indiana University School of Medicine. The study was funded by the National Institute on Alcohol Abuse and Alcoholism, the Office of Minority Health, and a General Clinical Research Center Grant.

Alcoholism: Clinical & Experimental Research

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