APOPTOSIS-RELATED GENETIC POLYMORPHISMS IN SARCOIDOSIS

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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. Granulomas are organized aggregations of the body's white blood cells, including lymphocytes and macrophages. Lung granulomas form in response to infectious agents, foreign materials and for unknown reasons. Sarcoidosis is a chronic granulomatous lung disease without a known cause. The mechanisms which promote the inflammatory response which eventually result in this disease process are not well understood. Observations of high rates of sarcoidosis in some families and specific ethnic groups has raised the question of a genetic basis for this disease. It is likely that individuals with a genetic background which predispose them to developing granulomas are more likely to develop sarcoidosis. Our study seeks to describe a possible mechanism by which granulomas may form, linking proteins potentially important in this process to genes which might increase susceptibilty to sarcoidosis. One set of genes that may be implicated are those involved in apoptosis, or programmed cell death. Apoptosis may be initiated by binding of a death receptor to a death ligand. A few studies have found apoptosis in granulomatous diseases, including sarcoidosis. Prelimanary data suggest that granuloma-inducing agents may also induce cell apoptosis. In sarcoidosis, high levels of two apoptosis proteins, Fas (CD95, Apo-1) and tumor necrosis factor (TNF, TNF-a, cachectin), are found. It is possible that apoptosis is important in the development of granulomatous inflammation. Our study quesions whether genetic differences in these two apoptosis genes might result in higher protein levels and apoptosis, and even increased susceptibility to sarcoidosis. Furthermore, if apoptosis is important in the development of this inflammatory process, it may result in more severe disease. In this study, we plan to evaluate the levels of Fas and TNF expression in individuals with sarcoidosis compared to healthy controls and determine whether these higher levels are associated with higher levels of apoptosis. We also will evaluate whether those subjects with sarcoidosis are more likely to carry specific variants of the Fas and TNF genes, which may be associated with higher protein and gene levels of Fas and TNF. Finally, we will determine whether these genetic variants are associated with a more severe disease process in sarcoidosis. This information will help us define genetic susceptibility factors which may predispose some individuals to the development of sarcoidosis and possibly more severe disease and a means by which this may occur.