Gene-on-gene interactions may influence risk for developing alcoholism

Marc A. Schuckit:

Not only do both genes and environment have an impact on the development of alcohol-use disorders, but now researchers have found that certain genes may influence scientists' ability to interpret other genes' effects. One variant of the alcohol dehydrogenase (ADH) gene – the ADH1B genotype – appears to be able to influence level of response (LR) to alcohol among non-Asians.

Results are published in the September issue of Alcoholism: Clinical & Experimental Research.

There are at least two known groups of gene mutations that can effect how individuals metabolize alcohol, explained 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 co- author of the study. One group of mutations is in an enzyme called aldehyde dehydrogenase (ALDH) and the other group is in the ADH enzyme. These mutations – predominantly observed among Asians – tend to impart protection from alcohol-use disorders because they cause a larger, more intense LR to alcohol, including facial flushing.

"The question was raised," continued Schuckit, "do the ADH mutations affect LR to alcohol in Caucasians? There are some fairly consistent reports in the literature that some Caucasians do have a bit of facial flushing with alcohol similar to what you see in Asians. Accordingly, if you can find this same increased response to alcohol in the roughly 10 percent of the Caucasian population that carries these ADH gene mutations, the next question is: 'how does that effect our ability to study people's LR to alcohol as it might be influenced by another gene?'"

For this study, participants numbered 117 (81 females, 36 males), ranging in age from 18 to 29 years of age, were primarily Caucasian (70.1%) and Black (26.5%), and recruited from San Diego, California. Researchers used various tools to assess demographic, substance use, psychiatric history, and first-degree family history of alcohol dependence. In addition, all participants provided a blood sample for genotyping, and were given an alcohol challenge in order to examine their LR to alcohol during a 210-minute session.

Results showed that participants with the ADH1B*1/*2 genotype had a higher LR to alcohol early in the alcohol challenge (that is, 30, 60 and 90 minutes after drinking), as measured by subjective feelings of intoxication and body sway.

"These findings suggest that there indeed might be a genetically influenced factor of a possible mildly increased LR to alcohol associated with the two genes that we studied," said Schuckit, "and that may decrease some people's risk for alcoholism slightly."

Schuckit said that these findings will likely change how he approaches his own research in the future. "In the kind of work that I'm doing, I had better evaluate people with those two gene forms of ADH separately, because I think they may wash out the effects of some of the other genes that I'm trying to look for. For the field in general, it's important for researchers to know that there are milder effects of alcohol-metabolizing enzymes similar to what's seen in Asians that might have an effect of slightly decreasing the risk for alcoholism."

He added that the implications of these findings go beyond significance for just researchers. "This is the sort of finding that reinforces the fact that genes impact on your response to alcohol, and impact on your risk for alcoholism," he said. "There are some people who think it's hard to see behavioral problems like alcoholism being impacted by genes, but of course it is, because genes affect what you were like before you took the alcohol, and also genes absolutely impact on how the alcohol will affect you. The clearest example we have of this are the alcohol-metabolizing genes."

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