Recent data from four independent sources suggest that genes on chromosome 1q are likely to play an important role in SLE. Tsao et al (J. Clin. Invest. 99:725,1997), Harley and Moser (Project #2), Behrens (Project #1) and Kimberly et al (J. Clin. Invest. 97:1348,1996; J. Clin. Invest. In Press, 1997) each have data which underscore the potential relevance of SLE to candidate regions on chromosome 1. However, the identification of a chromosomal region of interest is only the first step in the process of identifying the genes responsible for SLE, and it is likely that at least some of the molecules currently known to be involved in the immune dysregulation in SLE will be polymorphic and contribute to SLE genetic predisposition. Building on our preliminary data revealing polymorphisms in several relevant candidate genes in the region of 1q21 through 1q32 and on mapping data available through Projects #1 and #2, this project will identify candidate polymorphisms, characterize their biologies, and analyze their contributions as markers and disease related molecules. In conjunction with Projects #1, #2 and #4 and with the essential support of the Genetic Epidemiology and Biostatistics Core, this project will evaluate candidate genes for linkage and association in sib-pairs, multiplex families nd trio(simplex) families. Furthermore, this project will work with Project #4 to test the utility of these candidates are predictors of disease phenotype in the carefully characterized longitudinal PROFILE cohort of SLE patients. Through the shared resources embodied in this SCOR application, we will have the capacity to develop an understanding of how lupus genes affect disease expression and how that disease expression varies among ethnicities. This understanding will facilitate a more targeted application of current therapy and the development of new, mechanism-based therapies. These advances are possible only through the multi- disciplinary, team effort of this SCOR.
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