Identifying IBD risk alleles using haplotype analysis

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），在发达国家的合并患病率约为100-200/100，000。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（lambda's）的相对风险估计为CD的30-40倍和UC的10-20倍。这两种疾病都涉及肠粘膜内促炎细胞因子和免疫调节细胞因子的表达改变。我们实验室先前的研究涉及染色体5 q31上细胞因子基因簇中的一个位点，我们已经在该区域内对人类基因组进行了首次广泛的高分辨率单核苷酸多态性（SNP）分析。除了发现一种新的CD风险因子外，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的连锁峰到250 kb的片段，其中一个共同的单倍型（存在于超过75%的CD患者中）最终显示出具有显著的风险。对这种遗传变异结构的了解构成了目前建议的基础。 包括我们自己在内的几个研究小组已经确定了另外两个区域，可以说是迄今为止IBD最强的连锁证据，染色体19 p13和6p 21。在目前的建议中，我们的目标是确定单倍型结构的染色体6和19，并确定因果遗传变异赋予IBID的易感性。首先，我们将收集来自魁北克省的1000多名IBD患者的大量、仔细分型的样本，该地区有已知的创始人群。将与魁北克IBD遗传学联盟（QIGC）一起进行采集。其次，我们将使用全人类基因组序列所支持的遗传学方法对遗传变异进行全面分析，这是对遗传变异的新理解。大规模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遗传疾病的最大希望。

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.