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

染色体 3p 和 6p 上 IBD 基因的鉴定

• 批准号: 6802205
• 负责人: John D. Rioux
• 金额: $ 64.43万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-15 至 2007-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802205
• 关键词: clinical research; genetic mapping; genetic susceptibility; human tissue; inflammatory bowel diseases; single nucleotide polymorphism

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.

描述（由申请人提供）：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，其总患病率约为每 100,000 人 100-200 人。这两种疾病都涉及肠粘膜内促炎和免疫调节细胞因子表达的改变。然而，CD 和 UC 的临床和病理特征是不同的。流行病学研究揭示了 IBD 发病机制的显着遗传因素。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 IBD 遗传易感性。选择这些区域是因为在多次全基因组扫描中观察到重复的连锁证据，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 区域包含人类白细胞抗原 (HLA) 基因簇，其与 IBD 的许多关联已被报道，但致病变异尚未确定。 我们实验室之前的研究首次对人类基因组进行了广泛的高分辨率 SNP 分析。具体来说，我们通过对染色体 5q31 细胞因子基因簇中 8 个个体的 470 kb（总序列>3.7 Mb）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为进行关联研究提供强大的方法。该方法的成功应用使得能够鉴定 5q31 细胞因子基因簇中的遗传变异，该变异赋予克罗恩病的易感性。在当前的提案中，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 上的连锁区域的范围，并确定导致 IBD 易感性的因果遗传变异。