Interaction between genetic background and oxidative environmental stimuli in the pathogenesis of human lung disease has been largely unexplored. Biological response to oxidative stress is a key mechanism in numerous inflammatory diseases. In this new study (which has been done at Johns Hopkins and will be transferred to NIEHS), we have begun a strong collaboration with Drs. Francine Kauffmann and Rachel Nadif (INSERM, Paris) to investigate the genetic basis of susceptibility to coal workers' pneumoconiosis (CWP) in individuals differentially exposed to coal dust and cigarette smoke. Drs. Kauffmann and Nadif have undertaken a prospective epidemiologic in 253 coal miners, which included quantitative phenotypes of response to environmental stimuli that may be involved in CWP, an inflammatory lung disease. Six oxidative stress markers were studied as intermediate phenotypes of response to exposure, including erythrocyte glutathione peroxidase (GSH-Px) and catalase activities. Oxidant exposures studied were smoking habits and cumulative dust exposure assessed by job history and ambient measures of exposure. Disease phenotypes included subclinical computed tomography score at the first survey and X-ray profusion grades twice 5 years apart to assess established CWP. My laboratory has obtained bloods from each of the individuals recruited to the study and DNA was isolated. We will investigate the genetic basis for CWP susceptibility by evaluating association of selected phenotypes with polymorphisms in the following """"""""classes"""""""" of genes: innate immunity, inflammation, and antioxidant. In the present study, miners were genotyped for common functional polymorphisms in the gene for tumor necrosis factor a (TNF) and lymphotoxin a (LTA), two proinflammatory cytokines that have been implicated in the pathogenesis of chronic lung disease. Regarding gene-environment interaction on intermediate phenotypes, our results showed interaction of the -308 promoter polymorphism in TNF with occupational exposure on erythrocyte GSH-Px activity with a significant association in those with high exposure (p = 0.003) whereas no association was observed among those with low exposure (interaction p = 0.06). Regarding gene-intermediate phenotype interaction on clinical outcome, our results showed an association of CWP prevalence with the NcoI polymorphism in LTA in those with low catalase activity (p = 0.05) whereas no association was observed in those with high (a priori protective) activity (interaction p = 0.03). No significant association was observed with Cu++/Zn++SOD or plasma GSH-Px activities. Results suggest that interactions of genetic background with environmental exposure and intermediate response phenotypes are important components in the pathogenesis of disease (CWP) in coal miners.
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