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Looking for the genes that affect a person's level of response to alcohol

How a person "feels" the effects of alcohol is, in part, genetically influenced and relates to their risk for developing alcoholism. A low level of response (LR) to alcohol, or the need for a higher number of drinks to feel intoxication the first few times a person drinks, is more likely to occur in children of alcoholics, and predicts a greater risk for alcohol problems. A study in the November issue of Alcoholism: Clinical & Experimental Research has found that a gene on chromosome 10 ?in particular, the KCNMA1 gene ?is potentially linked to LR.

"The LR to alcohol is a genetically influenced phenotype, or measurable characteristic, that contributes toward the development of alcoholism," said Marc A. Schuckit, director of the Alcohol Research Center, Veterans Affairs San Diego Healthcare System, professor of psychiatry at the University of California, San Diego, and first author of the study. "The earlier you study it, the better. We tested people with alcohol challenges to look at their LR at the youngest possible age they could give informed consent as the picture is clearest when they're youngest. When people get older, they get fatter, they change their percent body water, which changes their reaction per drink, their liver gets a little slower in metabolizing alcohol, their brain gets a little more sensitive to alcohol, and when they get sick, they take medications, all of which affects their LR to alcohol."

Furthermore, added Victor Hesselbrock, professor of psychiatry at the University of Connecticut School of Medicine, "young individuals, particularly teenagers and young adults, feel that being able to 'hold one's liquor' is a good thing. Yet we in the scientific and clinical community know that high rates of consumption at any age lead to poorer outcomes, both in terms of psychosocial as well as medical functioning. While some individuals might say 'I'm not an alcoholic' or 'I'm not one of those down and out alcoholics,' the truth is that high levels of alcohol consumption over time have an impact on the immune function, liver, gastrointestinal system, etc. and we know that people are just not immune to that."

For this study, researchers examined 238 18-to-29-year-old pairs of siblings (about 365 people) who had at least one alcohol-dependent parent. All of the pairs of siblings had had some experience with alcohol use themselves, but were not yet alcohol dependent. The goal was to both measure their LR to alcohol and evaluate how their LR related to specific regions of chromosomes.

LR was established through use of the Subjective High Assessment Scale as well as measurements of body sway. "We looked at almost everything a person could feel after they drink alcohol ?whether dizzy, nauseated, happy, intoxicated, whatever ?and we asked the subjects to rate each one of these feelings from 0, meaning not at all, to 36, meaning the most they could imagine," said Schuckit.

"What's interesting about this design is that researchers used what we would say are two separate phenotypes," said Hesselbrock. "One is the person's subjective opinion of feeling intoxicated, which is the scale used, and the other one is an objective behavioral measure, which is body sway. We know that as people get intoxicated, their ability to stand still is impaired, so that they actually do move back and forth."

In addition, all of the participants supplied blood samples that were used to look for linkages of their LR characteristic to selected chromosomal regions.

Results indicate that an area on chromosome 10 is potentially linked to LR, in particular, the KCNMA1 gene. These results are particularly interesting, said Schuckit, because prior research had indicated a potential link between this section of this chromosome and a person's alcohol response.

"Researchers in San Francisco had previously carried out some research on worms," explained Schuckit, "fin ding that those worms with a mutation in that gene were fairly insensitive to alcohol. We also knew that alcohol has an effect on what this gene controls, which is potassium flow. Our current results appear to show that the corollary of this gene in humans helps to control the intensity of the effects of alcohol on the flow of potassium in and out of cells."

"We know that alcoholism/alcohol dependence is a complex trait, and that the risk for it is composed of many, many different genes, each contributing a small to a medium amount," said Hesselbrock. "What Dr. Schuckit has done is add another set of genes to that pool. It may be a small step, but that certainly doesn't diminish the importance of the finding."


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