This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The interplay between exposure and genetic susceptibility factors 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, which also providing a model of gene and environment interactions for other lung disease. Inhalation of beryllium particles triggers an 'allergic' response or sensitivity to beryllium (BeS) and the scarring lung disease chronic beryllium disease (CBD) in 2-10% of exposed workers. A normal variant the human leukocyte antigen (HLA)-BPBI gene with an amino acid, glutamic acid at 69 (Glu69), has been found in 85-97% of cases of BeS and CBD compared to 30-45% of beryllium exposed non-diseased (Be-non-diseased) workers. It is likely that CBD is a multigenetic 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, including Glu69 and a variant of the TNF promoter gene (-308A), interact with each other and with exposure factors in the development of BeS, CBD and more severe CBD. Our study will determine if there is an interaction between the Glu69 gene variant, and the variant associated with an increased inflammatory response, the -308 TNF variant. Furthermore, this project will define exposure variables important in the development for BeS and CBD, and the relationship between these exposure variables and susceptibility genes in BeS and CBD risk.
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