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性疾病， 给患者和社会带来沉重的健康负担。通过全基因组关联研究（GWAS），在剖析IBD遗传病因学方面取得了巨大进展，鉴定了100多个IBD基因座，但主要限于欧洲血统的人。IBD遗传学联盟（IBDGC）的成立是为了促进6个遗传学研究中心（GRC）与数据协调中心（DCC）的多中心合作研究。我们在约翰霍普金斯的GRC（JHGRC）为所有IBDGC研究做出了贡献，领导了IBD中最大的全基因组连锁研究，并领导了IBDGC专注于非洲裔美国人（AA）IBD遗传学（招募了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、NOD 2和其他四个最具特征的CD遗传位点的混合物的评价。需要对AA IBD进行更多的研究，以了解这一祖先独特的主要美国人群中IBD的病因，并且还因为多样化的等位基因和单倍型结构以及独特功能变体的潜力将为所有人群带来益处。此外，一个主要的挑战，特别是对非编码协会，是要知道哪些SNP是因果关系与那些连锁不平衡。比较群体间的关联模式和评估映射到IBD相关细胞中活性的潜在转录因子（TF）位点的相关SNP的功能将是有益的。我们在下一个资助期的目标是（1）促进AA人群中更全面的IBD基因发现和评估，以及（2）表征IBD相关的表观基因组，并评估人群中最具挑衅性的非编码SNP，这些SNP映射到潜在的TF结合位点以改变基因组功能。对于第一个目标，我们已将招募扩大到12个卫星招募中心，并将在未来五年招募1000例AA IBD病例（潜在2600例）。AA中的免疫芯片IBD基因分型和第一阶段AA CD GWAS IBD正在进行中，第二阶段辅助R 01 AA CD GWAS计划在第3年与埃默里大学一起进行。我们将在第4年对1000例病例进行IBDGC AA UC GWAS。我们将比较不同种族间IBD的相关性，以确定最一致的非编码SNP。对于目标2，我们组建了一个团队来帮助我们表征IBD相关的表观基因组注释。我们将从患者切除的结肠中纯化免疫细胞，进行ChIP-Seq，并在转染细胞系中使用体外增强子测定评估映射到TF结合位点的SNP。我们将在IBDGC的所有活动中发挥重要作用， 通过我们的遗传统计学，基因组学，免疫学和微生物组共同研究者团队，通过我们获得生物材料（包括血液，活检，切除和粪便）和召回患者重新采样的能力，以及通过合作最大限度地提高IBDGC及其GRC和DCC的生产力。