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

描述（由申请方提供）：克罗恩病（CD）和溃疡性结肠炎（UC）是特发性炎症性肠病（IBD），在发达国家的合并患病率约为100-200/100，000。这两种疾病都涉及肠粘膜内促炎和免疫调节细胞因子的表达改变;然而，CD和UC的临床和病理特征不同。流行病学研究揭示了IBD发病机制的重要遗传贡献。受影响个体的兄弟姐妹的相对风险（ns）估计为CD的30-40倍和UC的10-20倍。 在本申请中，我们提出鉴定位于染色体区域3 p和6p的遗传变异，其赋予IBD的遗传易感性。之所以选择这些区域，是因为在多次全基因组扫描中观察到的重复连锁证据以及我们最近进行的荟萃分析中的强有力证据。此外，染色体6p区域含有人类白细胞抗原（HLA）基因簇，已报道了许多与IBD相关的基因，尽管致病变体尚未确定。 我们实验室先前的研究提供了人类基因组的第一个广泛的高分辨率SNP分析。具体地，我们通过对染色体5 q31的细胞因子基因簇中的8个个体中的470 kb（>总序列的3.7Mb）进行重新测序来进行SNP发现，并发现了人类基因组的潜在单倍型（单倍型=等位基因的特定组合）结构。我们最近证明，使用这种单倍型结构可以提供一个强大的方法来进行关联研究。该方法的成功应用使得能够鉴定赋予克罗恩病易感性的5 q31细胞因子基因簇中的遗传变异。在目前的建议中，我们的目标是利用基因组的单倍型结构来缩小染色体3 p和6p上的连锁区域，并确定赋予IBD易感性的因果遗传变异。

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.