Gene that affects alcohol sensitivity

Since one of the basic risk factors for alcoholism is a tolerance to alcohol, researchers have long sought to understand the genetic differences among people that affect their sensitivity to alcohol. So far, scientists have met with little success.

However, by exposing populations of the roundworm C. elegans to alcohol and pinpointing subtle genetic differences among strains that respond differently, researchers have identified one gene that affects alcohol sensitivity.

In an article in the June 10, 2004, issue of Neuron, Andrew Davies and his colleagues describe their findings that subtle differences between worm strains in the gene for a brain protein called NPR-1 explains differences in the worms' alcohol sensitivity.

The researchers chose the worm as their subject because there is evidence that alcohol has effects on worm behavior. Although the mechanisms that mediate alcohol response in humans or other animals are not well understood, most human neuronal proteins have worm versions and it seems likely that at least some of the mechanisms are shared. Additionally, the worm has been the subject of massive genetic study by scientists, and genetically distinct strains are available from around the world.

In their experiments, Davies and his colleagues exposed two wild strains of worms -- one from England and one from Hawaii – to alcohol and compared how they showed "acute tolerance" when first exposed to ethanol. The researchers used alcohol concentrations comparable to those that cause intoxication in humans.

The researchers measured the worms' responses by how much slower their movement became after exposure. The Hawaiian worms showed a more dramatic recovery from initial intoxication than did the English worms.

Genetic analyses of the two strains led to a subtle difference between the strains in the gene for NPR-1. The genetic difference, their experiments showed, caused production of higher levels of the NPR-1 protein in the alcohol-sensitive English worms, which decreased their ability to recover from alcohol exposure. While the researchers do not know the exact function of NPR-1, they do know that it appears to act as a neuronal receptor -- a molecular "socket" in brain cells into which plug proteins that affect signaling between brain cells.

The human relative of NPR-1, Neuropeptide Y (NPY), has been investigated as a potential genetic link to alcoholism but the data have been controversial. If further studies determine that NPY affects alcohol sensitivity, the researchers believe that determining genetic variation in the gene among people "may have direct relevance to our ability to predict susceptibility to alcoholism in humans.

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