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OHSU/VA Medical Center Researchers Track Gene Responsible for Alcohol Withdrawal

   Portland, Ore.

The research, which includes the identification of a suspect gene, may help determine a person's genetic predisposition to alcoholism

Scientists at Oregon Health & Science University and Portland Veterans Affairs Medical Center have made major advances in locating genes involved in alcoholism. Using mouse models, researchers are tracking down the genes that influence physical dependence on alcohol. One of these genes has been tracked to a small section of mouse chromosome four, a region containing approximately 15 genes. From that region, scientists are studying one specific gene that appears to be a particularly promising candidate. The finding draws scientists one step closer to identifying a specific gene involved in determining an individual's risk for alcohol withdrawal. The information could be used to provide better options in terms of intervention for those concerned about their risk of becoming dependent and those who are already dependent. Scientists in the Portland Alcohol Research Center (PARC), which comprises scientists from OHSU and the Portland VAMC, conducted the research. Their results were printed earlier this month in the Journal of Neuroscience.

Scientists are attempting to locate these withdrawal genes because previous research has shown that risk for becoming an alcoholic is associated with risk for symptoms of alcohol withdrawal. For example, individuals with a family history of alcoholism frequently report stronger withdrawal symptoms in the hours following alcohol consumption vs. patients without a family history of alcoholism. Scientists believe that by finding the genes responsible for alcohol withdrawal, it will be easier to determine which members of a family with a history of abuse are more likely to have chronic alcohol problems, and treat or counsel them before it's too late.

"In 1997 we identified at least three major genes on three different chromosomes that influenced risk for alcohol withdrawal. At the time, each of the chromosome regions contained hundreds of genes, any of one of which could have been responsible for a difference in risk for alcohol withdrawal. We've now made significant strides in determining the specific location of one of these genes. This research has significantly narrowed the list of suspect genes from about 1,000 to just 15. Moreover, we've identified one of these genes as a strong candidate" said Kari Buck, Ph.D., an assistant professor of behavioral neuroscience in OHSU's School of Medicine.

Scientists were able to locate the precise chromosomal region that harbors the withdrawal gene through the use of a series of congenic mice. These mice possess a small chromosomal segment (<1% of the genome) from one kind of mouse (for example, a strain at high risk for alcohol withdrawal) superimposed on a genome that is >99% from a different kind of mouse (such as a strain at low risk for alcohol withdrawal). Thus, a small region was effectively transferred from one strain to the other. The small region transferred varied, so by determining which mice actually showed more severe withdrawal from alcohol, and which did not, the scientists whittled down the size of the region that carried the withdrawal gene. In this way, the scientists were able to greatly scale down their search for the culprit gene.

Through this technique, scientists at OHSU and the Portland VAMC have identified a promising candidate gene that lies within the small segment of chromosome they have been studying. While scientists believe the gene, called Mpdz, may be the gene influencing risk for alcohol withdrawal, more research is necessary to prove that Mpdz, and not one of the other 14 genes in the same chromosomal region, is responsible for increased risk for alcohol withdrawal.

"Risk for alcoholism is clearly influenced by both genetic and environmental factors. An individual's genes are responsible for about 50 percent of their risk for alcoholism. Environmental factors, including whether or not they actually drink alcohol, makes up the other 50 percent of their risk. This information comes from twin studies, as well as adoption studies, which demonstrate an increased risk for severe alcohol-related problems in children of alcoholics who were adopted out, even if they have been raised without knowledge of their biological parents' problems," said Buck. "In our research, we are working to track down and identify the specific genes involved in alcohol withdrawal as well as other behavioral responses to alcohol that may also contribute in future development of alcoholism. With this information we will be able to improve our ability to effectively treat individuals experiencing alcohol withdrawal. Better yet, we may be able to target counseling or other effective interventions to give high risk individuals a better chance to avoid becoming dependent in the first place," said Buck.

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