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

描述(申请人提供)：克罗恩病(CD)和溃疡性结肠炎(UC)是特发性炎症性肠病(IBD)，在发达国家的总患病率约为100-200/10万。这两种疾病都涉及肠粘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。流行病学研究表明，IBD的发病与遗传因素有关。对受影响个体(Ns)的兄弟姐妹的相对风险估计为CD的30-40倍和UC的10-20倍。 在这一应用中，我们建议鉴定位于染色体3p和6p区域的遗传变异，这些变异赋予了IBD的遗传易感性。之所以选择这些区域，是因为在多个全基因组扫描中观察到了重复的连锁证据，以及我们最近进行的荟萃分析中的有力证据。此外，染色体6p区包含人类白细胞抗原(人类白细胞抗原)基因簇，已有许多与IBD相关的报道，尽管其因果变异尚未确定。 我们实验室以前的研究首次提供了对人类基因组的广泛的高分辨率SNP分析。具体地说，我们对染色体5q31的细胞因子基因簇中的8个个体(总序列为3.7Mb)进行了470kb的重新测序，发现了人类基因组的潜在单倍型(单倍型=特定等位基因组合)结构。我们最近证明，使用这种单倍型结构可以提供一种强有力的方法来进行关联研究。这种方法的成功应用使5q31细胞因子基因簇的遗传变异得以鉴定，该基因簇赋予克罗恩病的易感性。在目前的方案中，我们的目标是利用基因组的单倍型结构来缩小染色体3p和6p上的连接区，并确定导致IBD易感性的原因遗传变异。

DESCRIPTION (provided by applicant): Crohn's disease (CD) and ulcerative colitis (UC) are idiopathic inflammatory bowel diseases (IBD) that have a combined prevalence of approximately 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 (ns) 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.