Searching for biochemical markers in children of alcoholics

March 13, 2000

Research shows that both genetic and environmental factors contribute to the development of alcoholism. Individuals with a family history of alcoholism are themselves at greater risk of developing alcoholism, yet some children of alcoholics (COAs) develop the disease while others don't, even within the same environment. A study published in the March issue of Alcoholism: Clinical & Experimental Research has found that a hormone called beta-endorphin (B-E) may help identify which individuals have the particular genetic combination that places them most at risk of becoming alcoholics.

"Alcoholism, rather than a weakness of will," said Janice C. Froehlich, professor of medicine at Indiana University School of Medicine and lead author of the study, "is a disease that has biological components to it. We know that alcoholism tends to run in families and that individuals with a family history of alcoholism are more likely to develop alcoholism themselves. However, not all children of alcoholics become alcoholic, in part, because not all family members will inherit a combination of genes that increases risk for alcoholism." The challenge, she added, is to be able to identify specific individuals in families with alcoholism who are at the greatest risk for developing alcoholism. One approach is to study the response of B-E to alcohol consumption.

B-E is a hormone that is manufactured within the endogenous opioid system of the brain. It produces euphoria and acts like the body's own morphine, said Froehlich. Endorphin levels increase, for example, during childbirth, trauma and running (known as the "runner's high"). Endorphin levels also increase in response to alcohol drinking, and this hormone may contribute to feelings of well-being produced by alcohol.

"Prior work has shown that the beta-endorphin response to alcohol is greater and more prolonged in people with a family history of alcoholism," said Froehlich. "This suggests that the beta-endorphin response to alcohol may possibly predict, in a high-risk family, which people will abuse alcohol and which people won't. But before a hormone can be used as a biomarker of genetic risk for alcoholism, it must be demonstrated that the hormonal response can be inherited. Our study demonstrated that the beta-endorphin response to alcohol is heritable.

"This is the first report of the heritability of a hormonal response to alcohol," said Froehlich. "When taken together with several other lines of evidence, the study suggests that the beta-endorphin response to alcohol may be a new biomarker that can be used to identify specific individuals who are at high genetic risk for developing alcoholism."

Behavioral geneticists have used several approaches to study the influence of genetic and environmental factors on behaviors such as alcoholism, including adoption, twin, and genetic-marker studies. Adoption analysis is one of the more direct approaches. A person who has been adopted as an infant will likely share only genetic factors with his or her biological relatives, but will share common environmental factors with his or her adoptive relatives. In the popular twin-studies approach, monozygotic or identical twins are compared with dizygotic or fraternal twins, both groups having been raised in the same environment. Identical twins share all of their genes whereas fraternal twins, like ordinary siblings, share approximately 50 percent of their genes. These approaches have been especially helpful for assessing significant genetic influences. The genetic-marker approach seeks to identify those specific genes -- out of the 50,000 to 100,000 genes that comprise the "human genome" or human genetic material -- that may influence a person's likelihood of developing alcoholism.

Using the twin-study approach, Froehlich's paper adds to a growing body of research seeking to isolate a set of responses to alcohol that may be used as biomarkers to identify individuals who are at elevated genetic risk for developing alcoholism. One use of biomarkers is preventative. Researchers now believe there are at least two types of alcoholism, one of which is more affected by genetic factors than the other. Biomarkers could provide the basis for screening tests to allow early identification of those individuals who would benefit from early prevention. Biomarkers may also reveal information about the neurochemistry of alcoholism that can lead to the design of drugs to treat the disease.

Gary S. Wand, professor of medicine and psychiatry at Johns Hopkins University School of Medicine, believes Froehlich's study makes at least two important contributions to the field. The first is finding that the B-E response to alcohol has a strong hereditary component; the second is further demonstrating the involvement of the endogenous opioid system in alcoholism. Wand himself studies the effects of opioid antagonists in the brains of nonalcoholic COAs.

"This is a novel, important study," said Wand. "The findings highly suggest that people may be born with differences in their brain opioid function that lead them to this susceptibility. For more than a decade now, evidence has demonstrated that part of the biological vulnerability to alcoholism involves alcohol1s ability to activate opioid pathways within the brain."

In addition to its predictive qualities, noted Wand, B-E may also be causal in nature. "There is so much evidence now that the endogenous opioid system is involved in the reward for most drugs of abuse, including alcohol. This study helps substantiate the model which asserts that the endogenous opioid system is part of a biological mechanism involved in alcohol drinking and reward."

Notwithstanding the biological basis of alcoholism, Wand is wary of the disease model being used to forgive destructive behaviors such as driving while intoxicated or harming others while in an alcohol-induced rage. "Yes, these people are wired to a susceptibility," he said. "This doesn't mean that the person has no options, no control over it, that they're a victim completely."

Wand said that alcoholism is like diabetes, both are polygenetic disorders that create a vulnerability. "Say you have a diabetic who rebels, doesn't come in for care, doesn't regulate himself or herself, and they develop horrible complications like blindness, kidney disease, et cetera," he said. "It1s not their fault that they were dealt with a genetic deck to be susceptible to diabetes, but it is their fault that they don1t take ownership of the disease and seek help." The bottom line, he noted, is that, "as with any disorder, you have to accept that you have it andthen seek treatment."

Froehlich said she plans to continue to examine the importance of B-E in the development of alcohol abuse and alcoholism. The next step will be to look at the predictive nature of the B-E response to alcohol, explained Froehlich. B-E will be examined in people in high-risk families before they become alcoholics, and they will then be watched over time to determine whether a larger B-E response to alcohol is highly correlated with the development of alcoholism. Wand believes that future studies will also need to investigate if opioid levels in the brain can be altered to reduce the chances of developing alcoholism.

Co-authors of the Alcoholism: Clinical & Experimental Research paper included: R.W. Zink, Departments of Medicine and Physiology/Biophysics, Indiana University School of Medicine; T-K Li, Departments of Medicine and Biochemistry, Indiana University School of Medicine; and J.C. Christian, Department of Medical and Molecular Genetics, Indiana University School of Medicine. The study was funded by grants from the National Institute on Alcohol Abuse and Alcoholism.
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Alcoholism: Clinical & Experimental Research

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