Mapping genes for IBD by admixture LD in Puerto Ricans

描述(由申请人提供)： 通过基因组扫描方法的研究已经确定了10多个染色体区域，这些区域包含可能的IBD易感基因。已识别的IBD1基因(NOD2)只能解释一小部分克罗恩病(CD)患者，与溃疡性结肠炎(UC)无关。因此，存在其他导致IBD易感性的基因，并需要对其进行鉴定。与NOD2基因相比，其余基因座对IBD的易感性较低，这表明较弱的连锁证据和不同人群/研究之间的一致性较差。为了识别这些影响不大的基因，基于连锁不平衡(LD)的关联研究是选择的方法。然而，在高加索人口中，LD的范围和有用性受到人口历史的限制。因此，我们在这里提出了一种替代策略，通过利用波多黎各的混合群体来定位IBD基因-利用混合连锁不平衡(MALD)进行定位。这项研究的目的是通过缩小显示有足够连锁证据的选定染色体区域，然后使用病例对照和基于家系的方法进行精细定位来识别IBD易感基因。具体地说，调查人员将建立一个具有临床特征的波多黎各IBD患者(300UC、300CD、300名对照)和家庭(400个三联体)的小组；使用具有人群特异性标记的MALD缩小包含IBD假定基因座的选定染色体区域；评估与NOD2和血清学抗体(ANCA、ASCA、I2)的潜在相互作用/混杂效应；以及在狭窄区域和候选基因内用密集标记精细定位易感基因。通过覆盖重要的染色体区域，使用LD持续存在于较长染色体片段的混合群体，对足够的群体特异性标记进行基因分型，控制虚假关联，评估与其他因素的交互作用，并采用两阶段作图策略，该建议最大限度地增加了细化包含IBD易感基因的染色体区域的机会，从而增加了确定实际导致IBD发展的基因的机会。

DESCRIPTION (provided by applicant): Studies by the genome scan approach have identified over 10 chromosomal regions containing putative loci predisposing to IBD. The identified IBD1 gene (NOD2) can only explain a small percent of Crohn's disease (CD) patients and does not contribute to ulcerative colitis (UC). Thus, other genes that contribute to IBD susceptibility exist and need to be identified. Compared to the NOD2 gene, the remaining loci contribute a lower susceptibility to IBD as indicated by weaker linkage evidence and less consistency across populations/studies. To identify such genes with modest effects, association studies based on linkage disequilibrium (LD) are the method of choice. However, in the Caucasian population the extent and usefulness of LD is limited by population history. Therefore, we herein propose an alternative strategy to map the IBD genes by taking advantage of an admixed population in Puerto Rico - mapping by admixture linkage disequilibrium (MALD). The goal of this study is to identify IBD susceptibility genes by narrowing selected chromosome regions showing sufficient evidence for linkage, then performing fine mapping using both case-control and the family based approaches. Specifically, the investigators will establish a panel of clinically characterized Puerto Rican IBD patients (300UC, 300CD, 300control) and families (400 trios); narrow selected chromosomal regions containing putative loci for IBD using MALD with population specific markers; evaluate potential interaction/confounding effect with NOD2 and serological antibodies (ANCA, ASCA, I2); and fine map the susceptibility genes with dense markers across the narrowed region and within candidate genes. By covering important chromosomal regions, using an admixed population in which LD has been sustained at longer chromosome segments; genotyping sufficient population specific markers; controlling for spurious association; evaluating interaction effects with other factors, and employing a two-stage mapping strategy, this proposal maximizes the opportunity to refine the chromosomal regions that contain susceptibility genes for IBD, thus enhancing the opportunity to identify the actual genes that contribute to the development of IBD.