Genome research targets environmentally induced disease

Environmental Genome Project researchers announce progress in efforts to identify specific genetic variations that make some people more susceptible to disease triggers.

By Susan J. Landers, AMNews staff. May 5, 2003.

Washington -- Why don't all smokers get lung cancer? Why does one chemical plant worker contract leukemia while his co-worker doesn't? And in a world in which terrorism is attracting attention, why are some people more vulnerable to the nerve gas sarin than others?

All of medicine would like to know the answers to those questions, and researchers at the Environmental Genome Project are in hot pursuit.

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The project's goal is to identify genetic variations that make individuals more susceptible to environmental agents, such as cigarette smoking, chemicals, pesticides or even terrorist agents. The effort is orchestrated by the National Institute of Environmental Health Sciences in Research Triangle Park, N.C., one of the National Institutes of Health.

The project, like its more famous sibling, the Human Genome Project, marked a milestone in April.

While the Human Genome Project celebrated the completion of its genomic map, the environmental effort announced on April 16 that it had completed its first phase by resequencing and cataloging more than 200 environmentally responsive genes.

The Environmental Genome Project, which began in 1998, has so far identified 554 candidate genes that influence or have a strong potential to influence human susceptibility to environmentally induced disease. Two more phases of resequencing are scheduled in the future.

NIEHS researchers have characterized genes that confer susceptibility to cancer, heart disease, diabetes and asthma, the institute's director Kenneth Olden, PhD, announced during a conference held at the main NIH campus in Bethesda, Md.

As the human genome effort completed its instruction set for humans and began to wind down its work, Dr. Olden said the project is poised to answer the "what next?" question.

It should enable "the health science community to take a major step forward in understanding and potentially preventing environmentally induced disease in susceptible individuals," said Dr. Olden. "Perhaps the most important development in health care in the 21st century will be incorporation of knowledge of gene-environment interactions into public health and the practice of medicine."

The project could also allow environmental health regulatory agencies to better craft rules regarding exposure levels to known harmful substances rather than applying a one-size-fits-all rule, he added.

Plotting variations

Many diseases are the outcome of a complex interplay between multiple genetic and environmental factors. "We know that multiple genes contribute to our potential susceptibility," said Debbie Nickerson, PhD, associate professor in the Dept. of Genome Science at the University of Washington School of Medicine in Seattle. One of the things that is being looked at now is a completed pathway where each individual gene makes its own contribution.

Most advances in understanding genetic diseases have been made in diseases caused by a mutation in a single gene, such as cystic fibrosis. The NIEHS project aims at identifying and characterizing the gene polymorphisms, or inherited variations, susceptible to environmental agents. The knowledge would then be used to protect identified individuals from disease and reduce adverse exposure and environmentally induced disease.

The 554 genes identified by the project as good candidates for sequencing are likely to grow as more genes are identified. Environmentally responsive genes tend to fall into categories. The 200 genes sequenced in the first phase are those that regulate DNA repair and cell cycle.

DNA repair genes influence the outcome of exposure to environmental agents that cause DNA damage. Individuals with higher or lower capacity for DNA repair have decreased or increased risk of certain types of environmental disease.

Genes that regulate cell cycle control the ability of a cell to proliferate, grow and differentiate. Changes in the progression of a cell through the cell cycle can increase the ability of the cell to survive stress, for example, by allowing cellular damage to be repaired prior to cell division.

The next phase of the project will focus on resequencing genes that regulate metabolism, cell signaling and cell death, or apoptosis.

The technology explosion in the genetics field helped the project greatly, noted Samuel Wilson, MD, NIEHS deputy director. The planned $60 million project came in under budget at a quarter of that amount, he said.

NIEHS funds five university-based centers working on the project. Some of their research highlighted at the conference:

• A University of Washington Division of Medical Genetics' study examining the role of the PON1 polymorphism and carotid artery disease.
• A University of Cincinnati investigation into polymorphisms associated with risk of severe heart failure and the effectiveness of albuterol on certain asthma patients.
• A University of California, Berkeley, Division of Environmental Health Sciences at the School of Public Health study of the role of folate in adult acute lymphocytic leukemia among susceptible individuals.
• A Georgetown University study of higher risk of prostate cancer in men with the genetic polymorphism of NKX3.1, a gene specifically expressed in the prostates of adult men.

The Environmental Genome Project is also developing five regional mouse genomic centers that will construct animal models containing various susceptibility genes to examine the role of gene-environment interaction in disease.

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