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超过10个染色体区域含有推定的IBD易感基因座。已鉴定的IBD 1基因（NOD 2）只能解释一小部分克罗恩病（CD）患者，而不会导致溃疡性结肠炎（UC）。因此，其他基因，有助于IBD易感性存在，需要加以鉴定。与NOD 2基因相比，其余基因座对IBD的易感性较低，如较弱的连锁证据和人群/研究之间的一致性较低所示。要确定这样的基因与适度的影响，关联研究的基础上连锁不平衡（LD）的方法的选择。然而，在高加索人群中，LD的范围和有效性受到人群病史的限制。因此，我们在此提出了一种替代策略，利用混合人口在波多黎各-混合连锁不平衡（MALD）映射IBD基因的地图。本研究的目的是通过缩小选择的染色体区域显示足够的连锁证据，然后使用病例对照和基于家族的方法进行精细定位来识别IBD易感基因。具体而言，研究者将建立一组具有临床特征的波多黎各IBD患者（300 UC、300 CD、300对照）和家庭（400 trios）;使用具有群体特异性标记的MALD缩小包含IBD推定基因座的选定染色体区域;评价与NOD 2和血清学抗体的潜在相互作用/混杂效应（ANCA，ASCA，I2）;以及用密集标记物在狭窄区域和候选基因内精细定位易感基因。通过覆盖重要的染色体区域，使用混合群体，其中LD在较长的染色体片段上持续存在;对足够的群体特异性标记进行基因分型;控制假关联;评估与其他因素的相互作用效应，并采用两阶段作图策略，该建议最大限度地提高了细化含有IBD易感基因的染色体区域的机会，从而增加了鉴定导致IBD发展的实际基因的机会。

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.