Identifying IBD risk alleles using haplotype analysis

描述(由申请人提供)： 克罗恩S病(CD)和溃疡性结肠炎(UC)是一种特发性炎症性肠病，在发达国家的患病率为100/10万~200/10万。流行病学研究显示，IBD的发病有显著的遗传因素，估计CD的兄弟姐妹(lambda‘s)的相对风险是CD的30-40倍，UC的10-20倍。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。我们实验室以前的研究发现在染色体5q31上的细胞因子基因簇中有一个基因座，我们首次在该区域内对人类基因组进行了广泛的高分辨率单核苷酸多态(SNP)分析。除了发现了一种新的CD危险因素外，我们还首次描述了人类基因组惊人的单倍型结构。了解这种单倍型结构使我们能够从18 cM的连锁高峰发展到250 kb的片段，其中一个常见的单倍型(存在于超过75%的CD患者中)最终被证明具有显著的风险。对这种遗传变异结构的了解构成了当前提议的基础。 包括我们自己在内的几个小组已经确定了另外两个与IBD有最强关联证据的区域，即染色体19p13和6p21。在目前的建议中，我们的目标是定义6号和19号染色体上的单倍型结构，并确定与同上同上的易感性有关的因果遗传变异。这个项目有两个主要目标。首先，我们将汇集来自魁北克省的1000多名IBD患者的大量、仔细的表型收集，魁北克省是一个已知创始人群体的地区。收集工作将与魁北克IBD遗传学联合会(QIGC)一起进行。其次，我们将使用遗传方法对遗传变异进行全面分析，这将使我们对人类基因组全序列有一个新的理解。一个庞大的临床联盟与最先进的研究遗传变异的方法相结合，代表了破译这些复杂的遗传病的最大希望。

DESCRIPTION (provided by applicant): 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. Epidemiological studies reveal a significant genetic contribution to the pathogenesis of IBD, with a relative risk to siblings of affected individuals (lambda's) estimated at 30-40 fold for CD and 10-20 fold for UC. Both diseases involve altered expression of proinflammatory and immunoregulatory cytokines within the intestinal mucosa. Prior studies in our laboratory implicated a locus in the cytokine gene cluster on chromosome 5q31, and we have performed the first extensive high resolution single nucleotide polymorphism (SNP) analysis of the human genome within this region. In addition to the discovery of a novel CD risk factor, we described for the first time the striking haplotype structure of the human genome. Understanding this haplotype structure enabled us to proceed from an 18 cM linkage peak to a 250 kb segment in which a common haplotype (present in greater than 75% of CD patients) was conclusively shown to confer significant risk. Knowledge of this structure of genetic variation forms the underpinnings of the current proposal. Several groups, including our own, have identified two other regions with arguably the strongest linkage evidence to date for IBD, chromosome 19p13 and 6p21. In the current proposal we aim to define the haplotype structure on chromosomes 6 and 19 and to identify the causal genetic variation conferring susceptibility to IBID. This project has two primary aims. First we will assemble a large, carefully phenotyped collection of over 1000 IBD patients from the Province of Quebec, a region with known founder populations. The collection will be performed together with the Quebec IBD Genetics Consortium (QIGC). Secondly we will perform comprehensive analysis of genetic variation using genetic approaches enabled by the complete human genome sequence an new understanding of genetic variation. The combination of a massive clinical consortium with state-of-the-art approaches to studying genetic variation represents the best hope for deciphering these complex genetic diseases.