Gene-environment interaction. (Headliners: NIEHS-supported research).

Effect of Polymorphisms on Biomarkers in Coal Miners

Nadif R, Jedlicka A, Mintz M, Bertrand J-P, Kleeberger S, Kauffmann F. 2003. 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 40:96-1.03.

Genetic polymorphisms have been implicated in the difference in response to environmental agents, but interactions between genes and environmental oxidants involved in the development of human lung diseases have been largely unexplored. Oxidative stress arising from cigarette smoking and long-term exposure to dust and particles causes chronic airway inflammation, which is essential to the development of many lung diseases such as asthma, chronic obstructive pulmonary disease, and coal workers' pneumoconiosis. In a study of 253 coal miners in France, NIEHS grantee Steven Kleeberger and colleagues investigated whether polymorphisms in two genes coding for the proinflammatory cytokines tumor necrosis factor [alpha] (TNF) and lymphotoxin-[alpha] (LTA) modify lung response to oxidants.

Specifically, the researchers measured intermediate biomarkers of response to oxidant exposure, including glutathione peroxidase (GSH-Px) and catalase activity in red blood cells among miners genotyped for the two polymorphisms. The researchers also gathered detailed information on the workers' cumulative dust exposure and smoking habits.

For miners with a promoter polymorphism at the -308 position in the TNF gene, the researchers observed a significant association with red blood cell GSH-Px activity at high oxidant exposure. No association was observed among workers with this polymorphism who experienced low exposure. Regarding clinical outcomes, the results showed a positive association for coal workers' pneumoconiosis among workers who had tow catalase activity and an Ncol polymorphism in the LTA gene. No association was seen in those with high catalase activity, nor were any other significant associations observed.

These results provide the first demonstration of the involvement of genetic polymorphisms of two genes in the control of physiotogic responses to exposure to oxidative stressors. The study suggests ah interaction of genetic background with environmental exposure, and further suggests that intermediate responses are important in the development and progression of chronic pulmonary diseases such as coal workers' pneumoconiosis.