Both environmental and genetic factors are involved in the risk for alcohol dependence. Genetically influenced characteristics are numerous, and include a low level of response (LR) to alcohol. A low LR to alcohol is reflected by relatively little effect at a given blood alcohol concentration, or through a self-report of numerous drinks required for specific alcohol effects. A study in the July issue of Alcoholism: Clinical & Experimental Research has identified three chromosomal regions in the human genome that appear to hold genes that affect low LR to alcohol.
"Prior research has shown that a significant proportion of the risk for having a low response to alcohol is genetic," said Kirk C. Wilhelmsen, principal investigator at the Ernest Gallo Clinic and Research Center and first author of the study. "In other words, most of what accounts for the variation among us in terms of our response to alcohol probably comes from genes. But the research doesn’t tell us how many genes are involved, or how the genes work to cause this effect."
"All behavior, thinking and feeling are controlled by the actions of molecules in the brain," added Ivan Diamond, professor and Vice Chairman of the department of neurology at the University of California, San Francisco. "Brain molecules can be changed by experiences in our environment, diseases, drugs and genes. Genes control the proteins which regulate the molecules that carry out all of the functions in the brain. If we could identify genes that confer risk for alcoholism or allow alcoholism to develop, then we could begin to understand which molecules are behaving abnormally or which molecules are responsible for contributing to alcoholism."
Diamond, who is also the founding director of the Ernest Gallo Clinic and Research Center, said that identification of chromosomes and eventually, specific genes, is a logical step in ongoing research. "About 25 years ago, Dr. Marc Schuckit started to measure responses to alcohol in young college students," he said. "None of these young men were alcoholics when they were tested. Many years later, however, he discovered that those young men who exhibited a low response to a drink of alcohol were more likely to become alcoholics in the future. Therefore, it seems that a diminished response to alcohol appears to predict the development of alcoholism in some people. If you are easily intoxicated by small amounts of alcohol, it is unlikely that you will ever become an alcoholic. On the other hand, if you can ‘hold your liquor’ at an early age, you have a greater risk of becoming an alcoholic years later."
For the current study, researchers initially chose participants from students attending two San Diego universities: each was between 18 and 29 years of age, had an alcohol-dependent parent, a personal history of drinking but not alcohol dependence, and a full sibling with similar characteristics. Full siblings (n=139 pairs) and available parents were then genotyped for 811 satellite markers. Subjects were given eight minutes to consume a beverage (20% by volume solution of 0.75 ml/kg of 95% alcohol for women and 0.90 ml/kg for men) from a closed container, designed to disguise the alcohol taste and the amount consumed. Measurements of body sway and both positive and negative subjective feelings were collected at baseline and then at 15 minutes, 30 minutes, and every half-hour thereafter during the three-hour testing session.
"We found there were three locations that had the largest evidence for genes that affect the level of response to alcohol," said Wilhelmsen. These were chromosomes 10, 11 and 22.
"Identification of chromosome locations for genes … that may affect someone's risk for becoming an alcoholic is important because this may lead to the identification of specific genes that determine how alcohol makes us feel, give us new insight into how the brain works, and help us understand why some people become addicted to alcohol," said Diamond.
"We still don’t know which genes or how many genes are involved," said Wilhelmsen. "What we do know is that there are some genes with big effects on the level of response to alcohol, and we know the approximate chromosome location. In terms of a puzzle, we now not only know which pieces contain the critical clues, we also know that probably the puzzle is solvable."
Next, Wilhelmsen and his colleagues will investigate if individual variations of these genes correlate with level of response to alcohol. "Each region that we’ve implicated typically contains about 200 to 300 genes," he said. "Because of the human genome project, we know a lot about some of the genes in this region, but some of the genes we know very, very little about. If we’re lucky, one of the genes that we think we understand something about will prove to play a role. However, if we’re unlucky, we’ll end up doing a systematic search of all the genes that are in the regions that have been implicated."
Funding for this Addiction Science Made Easy project is provided by the Addiction Technology Transfer Center National Office, under the cooperative agreement from the Center for Substance Abuse Treatment of SAMHSA.
Articles were written based on the following published research:
Wilhelmsen, K.C., Schuckit, M., Smith, T.L., Lee, J.V., Segall, S.K., Feiler, H.S., Kalmijn, J. (July 2003). The search for genes related to a low-level response to alcohol determined by alcohol challenges. Alcoholism: Clinical & Experimental Research, 27(8), 1041- 1048
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