Integrating Genetic and Environmental Information in Clinical Research

The risks posed by exposure to chemical and environmental agents are related to the level of exposure, the intrinsic potency of the agent, and the susceptibility of the person exposed. In general, the highest exposures are in patients receiving potent drugs or radiation as medical treatments and in workers manufacturing or cleaning up chemicals in various operations. Therefore, it is logical and efficient to investigate potential risks to human health in patients and in workers with known exposures to specific agents. Studies of risks to the general population from contamination of groundwater or from air pollution, consumer products, or hazardous waste sites are far more difficult to conduct because the levels of exposure are typically much lower and thus the likelihood of identifying adverse effects is significantly reduced. In addition, although chemical exposures may cause immediate toxicity to the skin, eyes, lungs, heart, liver, nervous system, reproductive organs, or other target sites in the body, some effects may be unrecognized at first, including mutations in specific genes that may eventually lead to cancer or birth defects. Repeated exposures at relatively low doses also may have cumulative toxic effects that are difficult to identify. The challenge of establishing that impairment of brain function can result from lead exposure, for example, illustrates the difficulty of assessing the role of chronic, low-level environmental exposures in disease.

These considerations highlight the importance of ecogenetic research combining careful exposure-assessment studies with investigations of genetic influences on disease. Such a multidisciplinary approach is being explored in a coordinated manner through the Environmental Genome Project (EGP), a research initiative supported by the National Institute of Environmental Health Sciences, a component of the National Institutes of Health. The goals of the EGP are to: (1) identify some of the more common genetic differences between individuals that appear to affect response to environmental hazards; (2) conduct epidemiological studies investigating the role of gene-environment interactions in the development of common diseases like asthma, cancer, and heart disease; and (3) promote the use of information regarding gene-environment interactions in public health initiatives.

The EGP will develop in several stages. In the first phase of the project, experts will identify a set of approximately 500 genes that appear to play a role in the development of environmentally-induced diseases. These will include xenobiotic metabolism and detoxification genes, DNA repair genes, signal transduction genes, and genes involved in oxidative processes. Having identified a set of genes that appear to be involved in environmental response, the second phase of the project will catalogue common genetic differences in these genes—differences that may affect the functioning of the associated enzymes. Finally, in the third phase of the EGP, researchers will study the biological implications of these genetic differences using functional assays and population-based studies of gene-environment interactions. Organizers of the project expect that the first two phases of the EGP will be completed in late 2004. The third phase of the project will require significantly more time to complete, however, and will involve numerous epidemiological studies conducted over the next ten to twenty years.

Since many of the genes believed to play an important role in how humans respond to environmental hazards appear to affect health only in the presence of specific environmental exposures, deciphering the relationships that exist between genetic variants and individual response has the potential to improve public health significantly. Identifying those persons most at risk, for example, and encouraging them to avoid those environmental hazards to which they are most susceptible, may help prevent or delay disease onset in large segments of the population without pharmacological interventions. In addition, projects like the EGP might eventually lead to:

1. more accurate estimates of disease risks;

2. targeted disease-prevention strategies or medical-

monitoring programs to detect disease earlier;

3. pharmaceutical products with fewer adverse effects; and

4. a better understanding of biological mechanisms of disease.

A great deal of work will need to be done to elucidate specific genetic risk profiles for environmentally-induced diseases as we move into the era of genetic medicine. In the meantime, both the population-wide approach that emphasizes environmental measures and the genetic approach that aims to identify individuals at increased risk are likely to be advocated. It is certainly prudent, for example, that everyone follow a diet that avoids excess fat, cholesterol, and salt. At the same time, genetic tests may soon be able to identify those persons at highest risk of developing coronary heart disease and high blood pressure. Taken together, these two strategies may provide a powerful approach to encouraging individuals to change their diets and lifestyles in ways that promote good health.

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