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Nature and Nurture in Disease
By Nancy Touchette

Environmental toxins, diet, behavior, and genes all affect susceptibility to disease.

Most people who develop lung cancer are smokers, but not all smokers get lung cancer. And not everyone who overeats develops diabetes. Cigarette smoke, diet, and other environmental influences cause disease in some people but not others. The Environmental Genome Project seeks to understand why our environment affects people so differently.

Scientists agree that most diseases are complex in origin, involving both genetic and environmental risk factors. With the human genome now sequenced, the Environmental Genome Project is using the information to tease out the complicated assortment of genetic variations, environmental exposures, and individual behaviors that collectively result in disease.

“We have been using models for disease that are too simple,” says Kenneth Olden, director of the National Institute of Environmental Health Sciences (NIEHS) in Research Triangle Park, North Carolina. “Many studies have focused on the role of genes, the environment, or behavior in causing disease, but never all three. We are now poised to do this.”

The Environmental Genome Project was initiated in 1997, as the human genome was being sequenced. Researchers at NIEHS recognized that there would be no single “human genome,” and that variations in genes underlie differences in people and how they respond to their environments.

“The excitement in the Human Genome Project is not in the similarity between individuals, but in the dissimilarity,” says Olden. “That’s where the action is.”

A major goal of the Environmental Genome Project is to catalogue variations in known gene sequences, particularly those genes that are likely to respond differently to environmental toxins.

The first phase of the project, completed this past April was to “re-sequence” more than 200 genes in 90 individuals and to identify variations in these genes. So far, more than 20,000 gene variants, or polymorphisms, have been identified.

The next step is to figure out how these differences in a person’s genetic makeup give rise to differences in their physical makeup. Researchers are looking at how some of these variants give rise to different proteins and how these proteins function differently in the cell.

For example, Clement E. Furlong, of the University of Washington in Seattle, has found two variations of the gene that encodes paraoxonase, an enzyme that breaks down certain pesticides and toxins. He is studying how various forms of the enzyme function differently.

Furlong finds that one form of the gene can influence whether or not a person is susceptible to the effects of sarin, a nerve gas that has been used as a bioterrorism agent. The same enzyme also metabolizes lipids in the body, and variations in the gene can affect susceptibility to coronary artery disease.

Researchers are also looking to the mouse to help them understand how variations in genes can affect function. The next phase of the Environmental Genome Project will be to insert gene variants into mice, and expose them to different environmental agents.

Eventually, this will help researchers understand why some people respond adversely to toxic substances, while others are unharmed. It will also help researchers figure out why some people respond differently to medications.

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