SLE and UC Study

本申请的长期目标是精确了解位于主要组织相容性复合体（MHC）中的遗传变异如何影响个体发展溃疡性结肠炎（UC）或系统性红斑狼疮（SLE）的风险;两种慢性炎症性疾病。MHC区域是染色体6p上的一个大区域，包含大约150个基因;其中许多基因在人类免疫系统中具有重要作用，包括人类白细胞抗原（HLA）基因。这样的理解将提高我们对导致这些和其他炎症性疾病的机制的认识， 提供了重要的疾病分子标记。以前的研究受到样本数量和适当遗传学工具可用性的限制。目前的建议利用了我们对人类基因组遗传变异模式的理解的最新进展。此外，该提议将利用MHC区域中遗传变异的非常高密度的图谱（大约每500-1000 bp 1个SNP）。该图谱将使选择信息丰富的SNP筛选集成为可能，以进行强大的关联图谱研究。该SNP筛选集将应用于大型充分表征的UC和SLE患者队列。相同的SNP筛选集也将应用于多种其他自身免疫性疾病。将对该屏幕中确定的区域进行全面的关联映射。此外，最近的工作已经证明了杀伤免疫球蛋白样受体（KIR）和HLA基因的等位基因的功能相关组合在影响人类免疫应答中的重要性。据信等位基因组合的这种影响部分地在NK细胞水平上起作用。鉴于新兴的 由于NK细胞在SLE中的重要性，我们将专门测试KIR/HLA组合与SLE易感性之间的关联。这项工作有望通过确定影响个体对溃疡性结肠炎或系统性红斑狼疮（两种慢性炎症性疾病）易感性的遗传因素，对公共卫生产生影响。这项工作也将提供重要的分子标记的疾病，可能是有用的，在临床管理这些衰弱性疾病。

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.