Identification of the IBD genes on chromosomes 3p and 6p

克罗恩病(CD)和溃疡性结肠炎(UC)是特发性炎症性肠病(IBD)。 在发达国家，每10万人中就有100-200人患有这种疾病。这两种疾病都涉及 肠黏膜内促炎症和免疫调节细胞因子的表达改变； 然而，CD和UC的临床和病理特征是不同的。流行病学研究显示， 在IBD的发病机制中有显著的遗传贡献。对受影响个体的兄弟姐妹的相对风险 (ZS)估计CD为30-40倍，UC为10-20倍。 在这一应用中，我们建议识别位于染色体区域3p和3p的遗传变异 6P是IBD的遗传易感基因。这些地区之所以被选中，是因为反复有证据表明 在多次全基因组扫描中观察到的关联，以及荟萃分析中的有力证据 我们最近表演了。此外，染色体6p区含有人类白细胞抗原(Has)。 已报道与IBD有许多关联的一组基因，尽管因果变异有 还没有确定身份。 我们实验室以前的研究首次提供了对人类的广泛的高分辨率SNP分析 基因组。具体地说，我们通过对8个个体重新测序470kb来执行SNP发现(&gt；3.7Mb，共 在染色体5q31的细胞因子基因簇中发现了潜在的单倍型 (单倍型=特定的等位基因组合)人类基因组的结构。我们最近展示了 这种单倍型结构的使用可以为进行关联研究提供一种强有力的方法。 这种方法的成功应用使5q31的遗传变异得以识别。 细胞因子基因簇，使人对克罗恩病易感。在目前的提案中，我们打算采取 利用基因组的单倍型结构缩小染色体3p上的连锁区 和6p，并确定易感IBD的原因遗传变异。

Crohn's disease (CD) and ulcerative colitis (UC) are idiopathic inflammatory bowel diseases (IBD) that have a combined prevalence of ,-,100-200 per 100,000 in developed countries. Both diseases involve altered expression of proinflammatory and immunoregulatory cytokines within the intestinal mucosa; however, the clinical and pathological profiles for CD and UC are distinct. Epidemiological studies reveal a significant genetic contribution to the pathogenesis of IBD. The relative risk to siblings of affected individuals (Zs) is estimated at 30-40 fold for CD and 10-20 fold for UC. In this application we propose to identify the genetic variation located in chromosomal regions 3p and 6p that confers genetic susceptibility to IBD. These regions were selected because of repeated evidence of linkage that has been observed in multiple genome-wide scans and strong evidence in a meta-analysis that we recently performed. Moreover, the chromosome 6p region contains the human leukocyte antigen (HLA) cluster of genes for which many associations to IBD have been reported, although the causal variants have yet to be identified. Prior studies in our laboratory provided the first extensive high resolution SNP analysis of the human genome. Specifically we performed SNP discovery by re-sequencing 470 kb in 8 individuals (>3.7 Mb of total sequence) in the cytokine gene cluster of chromosome 5q31 and discovered the underlying haplotype (haplotype = specific combinations of alleles) structure of the human genome. We recently demonstrated that the use of this haplotype structure could provide a powerful approach to performing association studies. The successful application of this approach enabled the identification of the genetic variation in the 5q31 cytokine gene cluster that confers susceptibility to Crohn's disease. In the current proposal we aim to take advantage of the haplotype structure of the genome to narrow down the linked regions on chromosomes 3p and 6p and to identify the causal genetic variation conferring susceptibility to IBD.