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Duke University

Center for Comparative Biology of Vulnerable Populations

Richard T Di Giulio, Ph.D.
richd@duke.edu
http://www.nicholas.duke.edu/ccbvp/ Exit NIEHS

Project Description

Despite the tremendous inter-individual variability in the response to environmental toxins, we simply do not understand why certain people develop disease when challenged with environmental agents and others remain healthy. Although an emerging consensus suggests that many of the complex and prevalent diseases that humans develop occur as a result of multiple biologically unique gene-gene and gene-environment interactions, this conceptual framework is limited. Environmental exposures affect those that are vulnerable temporally (age), spatially (geographically), and by unique circumstance (co-morbid disease, nutritional status, economic status, race, and genetics). Even this paradigm fails to address the complex interaction of endogenous and exogenous risks that ultimately cause disease. While the recent advances in human and molecular genetics provide an unparalleled opportunity to understand how genes interact with environmental stimuli to either preserve health or cause disease, without accounting for the temporal, spatial, and other unique components of an individual's microenvironment, our understanding of environmental health will remain incomplete. Thus, the theme of our Center is to understand how biological, physiological, and social aspects of vulnerability alter the effect of environmental toxins on human health. Specific goals of the Center are: 1. To develop and operate an interdisciplinary environmental health sciences research center with a focus on understanding how biological, physiological, and social aspects of vulnerability alter the effect of environmental toxins on human health; 2. To enhance research in environmental health at Duke by promoting research interactions between existing interdisciplinary programs in environmental health, fostering the development of new research loci in environmental health, and establishing an infrastructure to support and extend research in environmental health; 3. To identify new and creative policy approaches that combine advanced understanding of environmental health sciences with the reality of policy application; and 4. To serve as a technical and educational resource to the region, the nation, and to international agencies in the area of environmental health.

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Project Highlights

Gene-Environment Interactions and Asthma

The Pulmonary Biology and Disease Research Core, in collaboration with the Center’s Inhalation Toxicology and DNA Microarray Facility Cores, is currently involved in studies of the tumor necrosis factor (TNF) in human subjects. TNF is a proinflammatory cytokine, and TNF-α has been associated with increases in airway responsiveness in normal subjects. A polymorphism at position -308 of the TNF-α gene promoter has also been shown to be associated with increased risk of asthma. By pre-screening, a subject population homogeneous with respect to age was established. The population is 35% women; stratified by race, it is 36% African American, 56% Caucasian, and the remaining subjects Hispanic and Asian. Peripheral blood lymphocytes were isolated and DNA was extracted and the TNF-308 G>A polymorphism was determined by polymerase chain reaction fragment length polymorphism analysis (PCR-RFLP). Contingency tables for the association of TNF-308 genotypes with response indices to ozone were created for the Caucasian, and African-American populations. This analysis revealed among subjects that were heterozygotic or homozygotic for the -308 allele, vulnerability to ozone and the development of airway hyperresponsiveness was at least twice that of subjects with the wild-type TNF allele and differences were highly significant for the asthma indicator McH sensitivity. For the other two response indices, acute FEV1 change and epithelial permeability change, no association was found with -308 polymorphism genotypes, i.e., equal vulnerability was observed among all genotypes. Data analyses were stratified for race, since genotype frequencies are expected to vary by racial background. The African-American sample is smaller in size at this time (n = 43); however vulnerability of subjects with -308 allele and increased McH sensitivity following ozone, was still significant as compared to subjects with the wild-type allele.

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Genetic Polymorphism and NTD Risk 

The Neurobiology & Neurodevelopmental Disease Research Core has established a Folate Working Group comprised of 15 faculty and trainees from across the Duke University and the Medical Center. Several different disease entities are covered under this umbrella including psychiatric disorders, cardiovascular disorders, neurological disorders, traumatic brain injury, and several birth defects. Folate comprises an important environmental risk factor for many diseases under this umbrella. 

One example of folate-related disease is a common birth defect, neural tube defects. Familial studies indicate a significant genetic component to NTDs, with a 40-fold increase in risk in first-degree relatives (Elwood et al. 1992). Myriad environmental exposures have been implicated in the development of NTDs; most notably, a 50-70% decrease in risk can be achieved by maternal folic acid supplementation before conception. In a broad sense, this has been a major public health success story. However, not all NTDs are prevented by adequate folate supplementation, so individual-specific variation in response to folate supplementation, likely of a genetic nature, has been demonstrated. Thus, population-specific, blanket recommendations may need to be modified.

Recently, investigators in the Neurobiology & Neurodevelopmental Disease Research Core studied 28 polymorphisms in 11 genes from the folate metabolic pathway (Boyles et al. 2006) in a series of patients affected with spina bifida. The effects of polymorphisms in single genes, the effects of combinations of polymorphisms from multiple genes, and the effects of polymorphisms in the presence or absence of periconceptional maternal folate were examined. The most significant finding was that a polymorphism in BHMT (betaine homcysteine methyltransferase) is associated with NTD in these families, and that the results were more significant when mothers actively supplemented their diet with folate periconceptionally. These data suggest that some women with a specific BHMT polymorphism may increase their risk for having a baby with an NTD when they supplement their diet with folate periconceptionally – the current clinical recommendations for all women of reproductive age. In other words, these results suggest that the researchers may have identified women whose risk for having a baby with an NTD is increased as a result of overactivity in the folate metabolism pathway during early embryonic development.

Boyles AL, Billups AV, Deak KL, Siegel DG, Mehltretter L, Slifer SH, Bassuk AG, Kessler JA, Reed MC, Nijhout HF, George TM, Enterline DS, Gilbert JR, and Speer MC (2006) Neural tube defects and folate pathway genes: family-based association tests of gene-gene and gene-environment interactions. Environ.Health Perspect. 114 (10):1547-1552

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Last Reviewed: September 07, 2007