Gene-Environment Interaction: Effect of Polymorphisms on Biomarkers in Coal Miners

Steven Kleeberger*
The Johns Hopkins University Bloomberg School of Public Health
P01ES09606

Background: Oxidative stress is a harmful condition that occurs when there is an excess of free radicals, not enough anti-oxidants, or both. Studies have shown that free radicals contribute to many diseases including asthma and chronic obstructive pulmonary disease (COPD), diseases of the aging, such as Alzheimer's and Parkinson's disease, and tissue damage resulting from diabetes.

Genetic factors may also play a part in the susceptibility to oxidative stress. Genetic polymorphisms have been implicated in differences in responses to environmental agents, but the interactions between genes and oxidative environmental agents involved in the development of human lung diseases have been largely unexplored. The overproduction of reactive oxygen species (ROS) from cigarette smoking and long-term exposure to dust and particles causes chronic airway inflammation. Inflammation is essential in the development of many airway diseases such as asthma, COPD, and coal workers' pneumoconiosis (CWP). This research team decided to investigate whether polymorphisms in two genes coding for tumor necrosis factor (TNF) and lymphotoxin α (LTA), proinflammatory cytokines implicated in the progression of chronic lung disease, modify lung response to oxidants in an epidemiologic study of 253 coal miners.

Advance: A significant interaction was observed in miners with high oxidant exposure and a polymorphism in the TNF gene on red blood cell glutathione activity. No interaction was observed among workers with low exposure. Results also showed an association of CWP prevalence with a polymorphism in the Lta gene in workers with low catalase activity. Catalase is an enzyme that breaks down ROS like hydrogen peroxide. No association was seen in those with high catalase activity nor were any other significant associations observed.

Implication: These results provide the first demonstration of the involvement of genetic polymorphisms of two genes in the control of physiologic responses from exposure to oxidative stressors. The study suggests an interaction of genetic background with environmental exposure and intermediate responses are important in the development and progression of chronic pulmonary diseases such as coal worker's pneumoconiosis.

Citation: Nadif R, Jedlicka A, Mintz M, Bertrand JP, Kleeberger S, Kauffmann F. Effect of TNF and LTA polymorphisms on biological markers of response to oxidative stimuli in coal miners: a model of gene-environment interaction. J Med Genet. 2003 Feb;40(2):96-103.

* Present Address: Laboratory of Pulmonary Pathobiology, NIEHS