The interplay between exposure and genetic susceptibility has not been defined for many disease processes. This project will focus on exposure and genetic factors which result in beryllium disease, serving to better define risk factors in this disease process, while also providing a model of gene and environment interactions for other environmental lung disease. Inhalation of beryllium particular triggers sensitivity to beryllium (BeS) and the granulomatous lung disease chronic beryllium disease (CBD) in 2-10% of exposed workers. A polymorphism in the human leukocyte antigen (HLA) DPB1 containing a glutamic acid at amino acid position 69 (Glu69), has been found in 85-97% of CBD cases compared to 30-45% of beryllium exposed non-diseased (Be-non- diseased) controls. Preliminary data show that Glu69 is also associated with BeS, suggesting that Glu69 plays a role in the immune response to beryllium, not the development of disease per se. It is likely that BD is a multi-genetic disease, with a number of susceptibility factors determining BeS, CBD and more progressive forms of CBD. To date, information on other genetic susceptibility factors is limited, as is the relationship between genes and exposure. Preliminary data presented in this proposal indicate that high TNF-alpha levels, associated with an exaggerated immune response in CBD and more severe disease, are related to the TNF promote variant with an A at position -308 (-308A). The central hypothesis of this study is that immune susceptibility factors, including Glu69 and the -308A TNF promoter variant, interact with each other and with exposure factors in the development of BeS, CBD and more severe CBD. Preliminary data support the hypothesis that by increasing beryllium-stimulated TNF-alpha to high levels at the anatomical site of disease, the 308A allele may tip the scale in the direction allele may tip the scale in the direction of granulomatous inflammation, eventually resulting in progression from BeS to CBD and more severe diseases. The proposed study will determine if there is an interaction between the polymorphism associated with the development of the beryllium specific immune, Glu69, and a polymorphism associated with an increased inflammatory response via TNF-alpha, the -308 variant. Furthermore, this project will define exposure variables important in the development of BeS and CBD, and the relationship between these exposure variables and the Glu69 and -308A susceptibility genes in BeS and CBD risk.