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Mark of a drinker
Alcohol and the genome
Edward R. Winstead

Like any crutch, alcohol is only a temporary solution for a cell's real problem: defects in the genome.

By increasing the activity of an enzyme that is defective in many addicted drinkers, alcohol makes blood cells appear to function normally. A new study proposes that the missing activity could be a biological marker for individuals who are at risk for developing alcohol dependence. It appears that people who are missing some enzymatic activity may be using alcohol as a quick fix for a problem that originates in the genome, and studies are underway to characterize the genes involved.

"Certain individuals are born with less activity of the adenylyl cyclase enzyme," says Boris Tabakoff, chair of the Department of Pharmacology, University of Colorado School of Medicine, who led the research. "This enzyme is of interest because it has been implicated in the development of tolerance and dependence in drug abuse as well as alcoholism."

Tabakoff's team of researchers attempted to clarify the relationship between adenylyl cyclase, or AC, and alcohol dependence. AC is an important signaling mechanism for many kinds of cells. The enzyme, for example, gathers and relays information from outside the cell that is used during essential processes such as metabolism and gene regulation. The researchers used blood cells as surrogates for brain cells—a loss of activity due to a genetic defect will show up wherever the enzyme is expressed.

working backwards from marker to gene

In a population of 210 Australian men, the researchers found that AC activity is a marker for lifetime incidence of alcohol dependence. The study, which appears in the current issue of Alcoholism: Clinical & Experimental Research, took into account risk factors for alcoholism including cigarette smoking and depression. The researchers found no correlation between AC activity and cigarette smoking, age, or body weight. Individuals with a family history of alcohol dependence, a family history of major depression, or high levels of certain fats in the blood were more likely to have lower AC activity, however.

The AC enzyme comes in at least nine forms, two of which are prime suspects for determining enzymatic activity in this study. The genes for these enzymes have been identified, and several groups, including Tabakoff's, are looking for differences in these genes in various study populations around the world.

Twin and family studies since the 1980s have demonstrated the genetic component of AC activity. "This activity is genetically determined, but it can be influenced by other factors, such as alcohol," says Tabakoff. "One of the confounding issues in this kind of study is whether the person has been drinking or not." Precisely because alcohol influences AC activity, researchers have reported conflicting data over the years.

Dutch children inherit the marker

The current study may have an explanation. The effects of alcohol on AC activity, it turns out, can be detected for up to four days following a drinking episode. So analyzing blood that was donated within this window won't reveal the individual's true baseline. The researchers therefore concluded that AC activity may be a biological marker as long as the subject is abstinent for four days or more before testing.

Dutch children played a part in the discovery of the role of genes in AC activity. In a study of families in Amsterdam, children who had never sipped alcohol in their lives turned out to have low AC activity, according to Tabakoff. In another study, US researchers monitored enzyme activity over the course of several weeks in drinkers trying to quit. By analyzing the participants' blood at the start of the rehabilitation program, a few days later, and at the end of the program, researchers were able to see that alcohol affects enzyme activity for several days.

This study should be viewed as a prelude to further genetic studies, says Robert M. Anthenelli, of the College of Medicine at the University of Cincinnati. "The idea is that if one could identify a biochemical marker associated with drug or alcohol dependence or that is present in individuals with a dependence, then one could track backwards to see which genes are involved." The attention to the amount of time that subjects were abstinent and to the potential risk factors that could influence the results are strengths of this study, says Anthenelli, who also directs substance dependence programs at the Cincinnati Veterans Affairs Medical Center.

there is no single gene for alcoholism

Indeed, many more alcohol studies are inevitable. "One must stress that there's no one gene for alcoholism," says Tabakoff. "So even if we find that AC is associated with alcohol dependence, I would bet any amount of money that there will be more genes associated with alcohol dependence." Still, he adds, "every gene we find will add something to our understanding of this disease."

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Menninger, J.D. et al. Platelet adenylyl cyclase activity as a trait marker of alcohol dependence. Alcoholism: Clin Exp Res 24 (June 2000).

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