IBD Gene Mapping by Clinical and Population Subset

按临床和人群亚群划分的 IBD 基因图谱

• 批准号: 8549198
• 负责人: Steven R Brant
• 金额: $ 40.98万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8549198
• 关键词: Achievement; Active Sites; Admixture; African American; Alleles; American; Architecture; Area; Asians; Autoimmunity; Binding Sites; Biocompatible Materials; Biological Assay; Biopsy; Blood; Caring; Cell Line; Cells; Centers for Disease Control and Prevention (U.S.); ChIP-seq; Chromatin; Chromosome Mapping; Chronic; Clinical; Collaborations; Colon; Community Health Centers; Complex; Coupled; Crohn' s disease; DNA; DNA Repository; Data; Data Coordinating Center; Databases; Deoxyribonucleases; Disease; Disease Association; Enhancers; Epithelial Cells; Ethnic group; Etiology; European; Evaluation; Excision; Feces; Functional RNA; Functional disorder; Funding; Gastrointestinal Diseases; Gastrointestinal tract structure; Gene Expression Regulation; Genes; Genetic; Genetic Counseling; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Research; Genetic Risk; Genetic Variation; Genomics; Genotype; Goals; Haplotypes; Health; Hereditary Disease; Histones; Human; Immune; Immune System Diseases; Immunology; In Vitro; Individual; Inflammatory Bowel Diseases; Insulin-Dependent Diabetes Mellitus; Intestines; Investigation; Knowledge; Linkage Disequilibrium; Lymphocyte; Maps; Measures; Medical; Methylation; Molecular Genetics; Mutation; Patients; Pattern; Persons; Play; Population; Population Heterogeneity; Prevalence; Prevention strategy; Preventive; Procedures; Productivity; Publishing; Quality of Care; RNA; Recruitment Activity; Regulator Genes; Reporter; Research; Research Personnel; Resected; Resources; Risk; Role; Sampling; Serological; Single Nucleotide Polymorphism Map; Site; Societies; Staging; Structure; Study Subject; Study models; Systemic Lupus Erythematosus; T-Lymphocyte; Tissues; Ulcerative Colitis; Universities; Variant; Whole Blood; Work; cell type; cohort; disorder prevention; disorder risk; epigenome; epigenomics; gene discovery; genetic risk factor; genome wide association study; genome-wide linkage; high risk; histone modification; improved; in vitro Assay; interest; macrophage; microbiome; monocyte; next generation sequencing; novel; protein function; protein structure; risk variant; therapeutic target; transcription factor; transcriptome sequencing

DESCRIPTION (provided by applicant): Inflammatory bowel disease (IBD), Crohn's disease (CD) and ulcerative colitis (UC) are complex genetic disorders of the gastrointestinal tract, and a major health burden to patients and society. Tremendous progress has been made in dissecting IBD genetic etiology with identification of over 100 IBD loci by genome wide association studies (GWAS) but mainly limited to persons of European ancestry. The IBD Genetics Consortium (IBDGC) was established to facilitate multicenter collaborative studies of 6 Genetics Research Centers (GRCs) organized with a Data Coordinating Center (DCC). Our GRC at Johns Hopkins (JHGRC) has contributed to all IBDGC studies, led the largest genome wide linkage study in IBD and has led the IBDGC in a focus on African American (AA) IBD genetics (recruiting 88% of study subjects). We published the first large clinical characterization of AA IBD, serological associations of AA CD, clinical disparity studies, and most recently evaluation of admixture in AA CD, NOD2 the other four most well characterized CD genetic loci. More research in AA IBD is needed to understand the etiology of IBD in this ancestrally distinct, major American population, and also because diverse allelic and haplotype structure, and potential for unique functional variants will yield benefits for all populations. Additionally, a major challenge, especially for non- coding associations, is to know which SNPs are causative vs. those in linkage disequilibrium. Comparing association patterns across populations and evaluating function of associated SNPs that map to potential transcription factor (TF) sites active in IBD related cells will be beneficial. Our Aims in the next funding period are to (1) facilitate more comprehensive IBD gene discovery and evaluation in the AA population, and (2) to characterize the epigenome relevant to IBD and evaluate the most provocative non-coding SNPs across populations that map to potential TF binding sites for alterning genomic function. For the first Aim, we have enlarged our recruitment to12 satellite recruitment centers and will recruit 1000 AA IBD cases (with potential of 2600 cases) over the next five years. Immunochip IBD genotyping in AA's and a first stage AA CD GWAS IBD are underway, with facilitation of a 2nd stage ancillary R01 AA CD GWAS with Emory University planned for Year 3. We will perform an IBDGC AA UC GWAS of 1000 cases in year 4. We will compare IBD associations across ethnic groups to define most consistent non-coding SNPs. For Aim 2, we've assembled a team to help us characterize IBD relevant epigenomic annotation. We will purify immune cells from resected colon of patients, perform ChIP-Seq, and evaluate SNPs that map to TF binding sites using in-vitro enhancer assays in transfected cell lines. We will play a major role in all IBDGC activities, with our team of genetic statistical, genomic, immunology, and microbiome co-investigators, by our ability to obtain biological materials (including blood, biopsy, resection, and stool) and to recall patients for re-sampling, and by working cooperatively to maximize productivity of the IBDGC and its GRCs and DCC.

描述（由申请人提供）：炎症性肠病（IBD），克罗恩病（CD）和溃疡性结肠炎（UC）是胃肠道的复杂遗传疾病，A 患者和社会的重大健康负担。通过基因组广泛的关联研究（GWAS）鉴定超过100个IBD基因座，但主要限于欧洲血统的人，已经取得了巨大进步。建立了IBD遗传学联盟（IBDGC），以促进与数据协调中心（DCC）组织的6个遗传学研究中心（GRC）的多中心协作研究。我们在Johns Hopkins（JHGRC）的GRC为所有IBDGC研究做出了贡献，领导了IBD中最大的基因组广泛的链接研究，并领导IBDGC，重点是非裔美国人（AA）IBD遗传学（招募88％的研究对象）。我们发表了AA IBD的第一个大型临床表征，AA CD的血清学关联，临床差异研究以及最近对AA CD中混合的评估，NOD2，其他四个最有特色的CD遗传基因座。需要在AA IBD上进行更多的研究，以了解这个祖先与众不同的美国人口中的IBD的病因，也是因为不同的等位基因和单倍型结构，并且具有独特功能变体的潜力将为所有人群带来好处。此外，一个主要的挑战，尤其是对于非编码关联，是要知道哪些SNP是因果关系，而链接不平衡的挑战。比较跨种群的关联模式以及评估相关SNP的功能，将映射到潜在的转录因子（TF）位点活跃于IBD相关细胞中是有益的。我们在下一个资金期间的目标是（1）促进AA人群中更全面的IBD基因发现和评估，以及（2）表征与IBD相关的表观遗传组，并评估跨种群中最具挑衅性的非编码SNP，这些人群跨越了对潜在的TF结合位点映射的型号，以用于更改基因组功能。为了第一个目的，我们将招聘扩大到12卫星招聘中心，并将在未来五年内招募1000名AA IBD案件（潜力为2600例）。 AA的Immunochip IBD基因分型和第一阶段AA CD GWAS IBD正在进行中，并促进了第二阶段的辅助R01 R01 AA CD GWAS与Emory University计划为3年级。我们将在4年内进行IBDGC AA UC GWAS的1000案例。我们将在4年内进行1000个案例。我们将在IBD跨越一致的IBD SNPS中，以竞争IBD的一致性群体，以竞争IBD的一致性群体。对于AIM 2，我们组建了一个团队，以帮助我们描述IBD相关的表观基因组学注释。我们将使用在转染的细胞系中使用体外增强剂测定法对切除的患者结肠进行纯化的免疫细胞，进行CHIP-SEQ，并评估将SNP映射到TF结合位点。我们将在所有IBDGC活动中发挥重要作用， 通过我们获得生物材料（包括血液，活检，切除和粪便）的能力，通过我们组成的遗传统计，基因组，免​​疫学和微生物组共染色器，并通过协同工作以最大程度地提高IBDGC及其GRCS和DCC的生产率，使他们能够获得生物材料（包括血液，活检，切除和粪便）。