The long term objectives of this application are to obtain a precise understanding of how genetic variants located in the major histocompatibility complex (MHC) can influence an individual's risk to developing ulcerative colitis (UC) or systemic lupus erythematosus (SLE); two chronic inflammatory diseases. The MHC region is a large region on chromosome 6p that contains approximately 150 genes; many of which have important roles in the human immune system, including the human leukocyte antigen (HLA) genes. Such an understanding will improve our knowledge of the mechanisms that lead to these and other inflammatory diseases and may provide important molecular markers of disease. Previous studies have been limited by the number of samples examined and by the availability of appropriate genetics tools. The current proposal takes advantage of recent advances in our understanding of the patterns of genetic variation in the human genome. Furthermore, this proposal will take advantage of a very high density map of the genetic variation in the MHC region (approximately 1 SNP per 500-1000 bp). This map will enable the selection of an informative screening set of SNPs to perform a powerful association mapping study. This screening set of SNPs will be applied to large well-characterized UC and SLE patient cohorts. The identical screening set of SNPs will also be applied to multiple other autoimmune diseases. Comprehensive association mapping of the regions identified in this screen will be pursued. In addition, recent work has demonstrated the importance of functionally relevant combinations of alleles of the killer immunoglobulin-like receptor (KIR) and HLA genes in influencing the human immune response. It is believed that this influence of allelic combinations acts in part at the level of the NK cell. Given the emerging importance of NK cells in SLE, we will specifically test for association between KIR/HLA combinations and susceptibility to SLE. This work promises to have an impact on public health by identifying the genetic factors that influence an individual's susceptibility to ulcerative colitis or systemic lupus erythematosus, two chronic inflammatory diseases. This work will also provide important molecular markers of diseases that may be useful in clinical management of these debilitating diseases.
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