The long term objectives of this application are to obtain a precise understanding of how genetic variants located in the chromosomal region containing the SLAM family of cell surface receptors major can influence an individual's risk to developing systemic lupus erythematosus (SLE);a chronic and debilitating inflammatory disease. The MHC region is a large region on chromosome 1q that contains multiple genes that are involved in cell-cell interactions and control of the immune response in the human immune system. Such an understanding will improve our knowledge of the mechanisms that lead to this and potentially other inflammatory diseases and may provide important molecular markers of disease. This study takes full advantage of the knowledge of the patterns of genetic variation in the human and mouse genomes as well as the relevant technological platforms (laboratory and analytical). In particular this project takes advantage of the preliminary SNP haplotype map of the SLAM region that we have created as well as that of the International HapMap project in order to select the most informative set of SNPs for the screening phase of the association study. This screening set of SNPs will be applied to large well-charcterized SLE patient cohorts. Comprehensive association mapping of the regions identified in this screen will be pursued in the largest collection of SLE patients and controls (family- and population-based). In addition, recent work has demonstrated the importance of expression of different spice forms in susceptibility to autoimmune disease, however very little is known about the existence and expression patterns of splice forms of most genes in the genome. We will therefore characterize the gene expression pattern at the level of mRNA as well as cell surface protein expression in immunologically relevant cells from SLE patients and control individuals. This work promises to have an impact on public health by identifying the genetic factors that influence an individual's susceptibility to systemic lupus erythematosus, a chronic inflammtory disease. This work will also provide important molecular markers of diseases that may be useful in clinical mangement of this debilitating disease.
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