Genetics of Immune Pathways Leading to Severe Forms of IBD

导致严重 IBD 的免疫途径的遗传学

• 批准号: 8566100
• 负责人: Jerome I Rotter
• 金额: $ 28.73万
• 依托单位: CEDARS-SINAI MEDICAL CENTER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8566100
• 关键词: Amino Acids; Antibodies; Antineutrophil Cytoplasmic Antibodies; Binding Sites; Clinical; Clinical Course of Disease; Clinical Data; Cohort Analysis; Collaborations; Complex; Complex Genetic Trait; Crohn' s disease; Data; Disease; Disease susceptibility; Exons; Foundations; Genes; Genetic; Genetic Variation; Genotype; Goals; Haplotypes; IL17 gene; Immune; Immunophenotyping; Inflammatory Bowel Diseases; Logistic Regressions; Maps; Medicine; Messenger RNA; Methods; Modeling; Natural History; Onset of illness; Pathway Analysis; Pathway interactions; Phenotype; Program Research Project Grants; Protein Isoforms; Receptor Activation; Research Design; Risk; Role; Severities; Severity of illness; Staging; Susceptibility Gene; T-Cell Receptor; Technology; Testing; Translating; Ulcerative Colitis; Validation; Variant; Work; base; clinical phenotype; cohort; disease natural history; gene interaction; genome wide association study; hazard; member; model development; programs; promoter; response; success; trait; transcription factor

During the last cycle of this Program Project (PPG), genome-wide association study (GWAS) technology has created a revolution in complex genetics. We have contributed to many of the collaborations that have identified lists of susceptibility genes for common genetic traits, including specifically Crohn's disease (CD) and ulcerative colitis (UC). As is now well-known, Identification of a susceptibility gene provides clues, not only to variation within the identified gene, but also to additional genes and gene-gene Interactions that are pathway-related. Thus, as the GWAS revolution moved forward during the last cycle, we expanded our study of the genetics of IBD-related Immuno-phenotypes into two directions using haplotype-based analyses: (1) testing the role of GWAS-identified genes, and (2) testing genes In the same pathway as GWAS-identified loci. Furthermore, we have laid a foundation for this present cycle by completing a GWAS on over 1000 CD and over 900 UC subjects, with well-characterized clinical phenotypes and antibody expression data for ANCA, ASCA, anti-CBir1, anti-I2, and anti-OmpC (i.e. IBD Immuno-phenotypes) (with Project 2, 3 and Core B). As this PPG has demonstrated, these immuno-phenotypes are heritable and associated with IBD severity. We therefore propose a GWAS-identified pathway approach for unraveling the genetic contribution to the immuno-phenotypes and thus for clinical course and response to therapies. Given our preliminary data, we hypothesize that combinations of genetic variation in multiple genes in the Tcell receptor activation pathway are related to differences in both immuno-phenotypes and in disease course (i.e. IBD severity), and that this can be established in a pathway-directed two-stage study design. With the goal of identifying genes that contribute to immuno-phenotypes and thus IBD severity, we propose 3 Specific Aims: Aim 1- genotyping 4608 haplotype tagged and functional SNPs in a 2600 member discovery cohort; Aim 2 - genotyping 2304 SNPs in a 3400 member confirmation cohort along with trans-ethnic mapping; and Aim 3 - testing association with clinical features. This project will interact with the other projects (Projects 2 - 5) of the PPG by collaborating in the genetic aspects of their Aims.

在该计划项目（PPG）的最后一个周期中，全基因组关联研究（GWAS）技术在复杂遗传学领域引发了一场革命。我们为许多合作做出了贡献，这些合作已确定了常见遗传特征的易感基因列表，特别包括克罗恩病 (CD) 和溃疡性结肠炎 (UC)。众所周知，易感基因的鉴定不仅提供了已鉴定基因内变异的线索，还提供了与途径相关的其他基因和基因间相互作用的线索。因此，随着 GWAS 革命在上一个周期中向前发展，我们使用基于单倍型的分析将 IBD 相关免疫表型的遗传学研究扩展到两个方向：（1）测试 GWAS 识别的基因的作用，以及（ 2) 测试与 GWAS 识别基因座相同途径的基因。此外，我们通过完成对 1000 多名 CD 和 900 多名 UC 受试者的 GWAS 奠定了本周期的基础，其中包括 ANCA、ASCA、抗 CBir1、抗 I2 和抗 ANCA 的临床表型和抗体表达数据。 -OmpC（即 IBD 免疫表型）（包含项目 2、3 和核心 B）。正如该 PPG 所证明的，这些免疫表型是可遗传的，并且与 IBD 严重程度相关。因此，我们提出了一种 GWAS 鉴定的途径方法，用于揭示遗传对免疫表型的贡献，从而了解临床过程和对治疗的反应。根据我们的初步数据，我们假设 T 细胞受体激活途径中多个基因的遗传变异组合与免疫表型和病程（即 IBD 严重程度）的差异有关，并且这可以在以下途径中建立：定向两阶段研究设计。为了识别有助于免疫表型和 IBD 严重程度的基因，我们提出了 3 个具体目标： 目标 1- 在 2600 名成员发现队列中对 4608 个单倍型标记和功能性 SNP 进行基因分型；目标 2 - 对 3400 名成员确认队列中的 2304 个 SNP 进行基因分型以及跨种族定位；目标 3 - 测试与临床特征的关联。该项目将通过在其目标的遗传方面进行合作，与 PPG 的其他项目（项目 2 - 5）进行互动。