Mapping genes for IBD by admixture LD in Puerto Ricans

通过混合物 LD 绘制波多黎各人 IBD 基因图谱

• 批准号: 7123085
• 负责人: KENT D TAYLOR
• 金额: $ 39.54万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123085
• 关键词: Puerto Rican; chromosomes; clinical research; clinical trials; cooperative study; gene expression; gene mutation; genetic mapping; genetic markers; genetic susceptibility; genotype; human subject; inflammatory bowel diseases; linkage disequilibriums; quantitative trait loci

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.

描述（由申请人提供）： 基因组扫描方法的研究已经确定了10多个含有推定基因座的染色体区域，易于IBD。鉴定出的IBD1基因（NOD2）只能解释一小部分克罗恩病（CD）患者，并且不影响溃疡性结肠炎（UC）。因此，存在导致IBD易感性的其他基因，需要鉴定出来。与NOD2基因相比，其余的基因座对IBD的敏感性较低，如较弱的连锁证据和在人群/研究之间的一致性较小所表明的那样。为了识别具有适度效应的这种基因，基于连锁不平衡（LD）的关联研究是选择的方法。但是，在高加索人群中，LD的程度和有用性受人口历史的限制。因此，我们在这里提出了一种替代策略来绘制IBD基因的绘制，利用波多黎各的混合种群 - 通过混合链接不平衡（MALD）映射（MALD）。这项研究的目的是通过缩小选定的染色体区域来识别IBD敏感性基因，显示足够的链接证据，然后使用病例控制和基于家庭的方法进行精细映射。具体而言，研究人员将建立一组临床表征的波多黎各IBD患者（300UC，300CD，300CONTROL）和家庭（400个三重奏）；使用特定于人群的标记的MALD，狭窄的选定的染色体区域，其中包含IBD推定基因座；评估与NOD2和血清学抗体的潜在相互作用/混杂作用（ANCA，ASCA，I2）；并细微地绘制横跨狭窄区域和候选基因的易感基因。通过覆盖重要的染色体区域，使用LD在较长的染色体段中维持LD的混合种群；基因分型有足够的人群特定标记；控制虚假协会；该提案评估与其他因素的相互作用效果，并采用两阶段的映射策略，最大程度地提高了包含IBD易感基因的染色体区域的机会，从而增强了识别有助于IBD发展的实际基因的机会。