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: 7493699
• 负责人: John D. Rioux
• 金额: $ 11.17万
• 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 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7493699
• 关键词: 5q31; Affect; Alleles; Applications Grants; Arts; Bioinformatics; Candidate Disease Gene; Child; Chromosomes; Class; Clinical; Collection; Crohn' s disease; Cytokine Gene; Data; Dedications; Detection; Developed Countries; Developing Countries; Disease; Ensure; Epidemiologic Studies; Fathers; Gene Cluster; Genes; Genetic; Genetic Predisposition to Disease; Genetic Variation; Genome; Genomics; HLA Antigens; Haplotypes; Human Chromosomes; Human Genome; Human Genome Project; Individual; Inflammatory; Inflammatory Bowel Diseases; Institutes; Intestinal Mucosa; Laboratories; Link; Linkage Disequilibrium; Location; Maps; Massachusetts; Measures; Meta-Analysis; Mothers; Pathogenesis; Patients; Pattern; Phenotype; Predisposition; Prevalence; Principal Investigator; Quebec; Relative Risks; Reporting; Research; Research Personnel; Resolution; Resources; Risk; Role; SNP genotyping; Sampling; Siblings; Signal Transduction; Structure; Technology; Testing; Ulcerative Colitis; Variant; Work; base; cytokine; disorder control; experience; genetic analysis; genetic variant; genome wide association study; genotyping technology; human disease; human leukocyte antigen gene; leukocyte antigen typing; programs

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.

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 遗传因素对 IBD 的发病机制有重要影响。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。 在此应用中，我们建议鉴定位于染色体区域 3p 和 6p 赋予 IBD 遗传易感性。选择这些地区是因为有反复的证据表明 在多次全基因组扫描中观察到的联系以及荟萃分析中强有力的证据表明 我们最近表演了。此外，染色体6p区域含有人类白细胞抗原（HLA） 已报道了与 IBD 有许多关联的基因簇，尽管因果变异已被报道 尚未确定。 我们实验室之前的研究首次对人类进行了广泛的高分辨率 SNP 分析 基因组。具体来说，我们通过对 8 个个体的 470 kb（>3.7 Mb 总序列）位于染色体 5q31 的细胞因子基因簇中，并发现了潜在的单倍型 （单倍型 = 等位基因的特定组合）人类基因组的结构。我们最近展示了 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5q31的遗传变异得以鉴定。 细胞因子基因簇赋予克罗恩病易感性。在当前的提案中，我们的目标是 利用基因组的单倍型结构缩小 3p 染色体上的连锁区域范围 和 6p 并确定导致 IBD 易感性的因果遗传变异。