Genomics of Inflammatory Bowel Disease

炎症性肠病的基因组学

• 批准号: 10684936
• 负责人: Leah Claire Kottyan
• 金额: $ 74.61万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10684936
• 关键词: Alleles; Antineutrophil Cytoplasmic Antibodies; Autoimmune; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; BZLF1 gene; Binding; Binding Sites; Catalogs; ChIP-seq; Characteristics; Childhood; Colon; DNA; DNA Binding; Data; Data Set; Disease; Disease Resistance; Enhancers; Environmental Risk Factor; Epstein-Barr Virus Infections; Epstein-Barr Virus Nuclear Antigens; Epstein-Barr Virus latency; Etiology; Freezing; Gene Expression; Genetic; Genetic Predisposition to Disease; Genetic Risk; Genomics; Human; Human Herpesvirus 4; Immune system; Immunoprecipitation; Individual; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Informatics; Lesion; Letters; Libraries; Lytic Virus; Molecular; Mucous Membrane; Natural Killer Cells; Nuclear; Pathogenesis; Pathologic; Pathology; Pathway interactions; Patients; Peroxidases; Phenotype; Prevalence; Protein Biosynthesis; Protein Microchips; Proteins; Qualifying; Regulator Genes; SPI1 gene; Serology; Serum; Severity of illness; T-Lymphocyte; Techniques; Technology; Testing; Ulcerative Colitis; Viral; Viral Genes; Virus; Work; cell type; chromatin immunoprecipitation; disorder risk; experimental study; gene product; genome wide association study; improved; infected B cell; inhibitor; mRNA Expression; microbiome; next generation sequencing; novel therapeutics; programs; risk variant; therapy resistant; transcription factor; transforming virus

In Inflammatory Bowel Disease (EBV) Epstein-Barr virus (EBV) infection is thought to contribute to disease severity and resistance to therapy. Recently, we discovered a powerful association between the DNA immunoprecipitated by EBNA2 and the risk loci of IBD, intersecting 38 of 112 evaluated loci (from the GWAS catalog in 2015) (RR=3.3, Pc=1.24x10-13) (1). Newer data confirm the EBNA2 association and also show that EBNA3C and EBNALP ChIP-seq (chromatin immunoprecipitation with next generation sequencing) data are also associated with IBD loci (RR=2.3, Pc=2.3x10-12 & RR=2.3, Pc=2.3x10-12, respectively) while BZLF1 (ZTA), an EBV Lytic program transcription factor (TF), is not associated. EBNA2, EBNA3C, and EBNALP are expressed in the EBV Latency III program of viral gene expression, causing the infected B cell to transform and becoming a major target for incomplete destruction by the normal human immune system. Interestingly, human transcription factors (TFs) tend to bind the same loci that are bound by these Latency III EBV gene products, forming intersection clusters that identify the contributing, presumably, regulatory IBD loci. Our interpretation is that these associations strongly suggest that at the intersecting loci viral mechanisms commandeering the cellular phenotype are shared with the genetic mechanisms of IBD risk. We conclude that this relationship likely represents related molecular pathways. The question is whether these associations are correlations, reflecting converging but independent mechanisms, or whether these correlations are interdependent and exist because the virus is etiologic and involved in disease pathogenesis. Establishing either possibility would be a major advance for IBD with viral constituents being probes to dissect mechanism. If EBV infection is etiologic, then, perhaps, the initial EBV-related lesion interferes with the barrier function, allowing the endogenous microbiome to induce the inflammatory response that we recognize as one or more of the pathologies of IBD. Since other EBNA2 associated disorders are autoimmune (1) and some EBV associations with IBD severity are colonic, if EBV is etiologic, then the autoimmunity of Ulcerative Colitis (UC) would be a most likely suspect. We propose to: Aim 1.) Exploit the discovery of additional IBD risk loci; improvements in our informatics, including allele specific analysis; and the new chromatin immunoprecipitation data accumulated to redefine the associations previously discovered (1). Aim 2.) Better understand the genomic mechanisms of IBD by applying state-of-the-art genomic technologies. Aim 3.) Develop new therapeutics for IBD directed against EBV, particularly against the Latency III transforming expression program of EBV, and Aim 4.) Test the prediction of the etiologic possibility that EBV-infection is increased in IBD and, if so, then identify the characteristics of the IBD subset whose illness is related to the inflammatory pathology of IBD, perhaps those with autoimmune UC. This project will determine whether EBV is a plausible etiology for some IBD, characterize regulatory genomic mechanisms in risk loci, and initiate experiments to find new therapies to reduce the impact of EBV on IBD.

在炎症性肠病（EBV）中，爱泼斯坦 - 巴尔病毒（EBV）感染被认为有助于疾病 严重性和抵抗治疗。最近，我们发现了DNA之间的有力关联 由EBNA2和IBD的风险基因座进行免疫沉淀，与112个评估基因座相交的38（来自GWAS 2015年目录）（RR = 3.3，PC = 1.24x10-13）（1）。较新的数据证实了EBNA2协会，也表明 EBNA3C和EBNALP CHIP-SEQ（下一代测序的染色质免疫沉淀）数据是 还与IBD基因座（RR = 2.3，PC = 2.3x10-12＆rr = 2.3，PC = 2.3x10-12），而BZLF1（ZTA）， EBV裂解程序转录因子（TF）无关。 EBNA2，EBNA3C和EBNALP表示 在病毒基因表达的EBV潜伏期III程序中，导致感染的B细胞转化并成为 正常人免疫系统破坏不完全的主要目标。有趣的是，人类 转录因子（TFS）倾向于结合由这些潜伏期III EBV基因产物结合的相同基因座， 形成相交集群，这些簇鉴定出贡献的，大概是调节性的IBD基因座。我们的解释是 这些关联强烈表明，在相交的基因座病毒机制中 细胞表型与IBD风险的遗传机制共享。我们得出结论，这种关系可能 代表相关的分子途径。问题是这些关联是否是相关性，反映 融合但独立的机制，或这些相关性是否相互依存并且存在，因为 该病毒是病因，参与疾病发病机理。建立任何一种可能性将是主要的 IBD的前进，病毒成分是探针剖析机制的探针。如果EBV感染是病因，那么， 也许，最初的EBV相关病变会干扰屏障功能，从而允许内源性微生物组 为了诱导炎症反应，我们认为是IBD的一种或多种病理。自从其他 EBNA2相关疾病是自身免疫（1），如果 EBV是病因，那么溃疡性结肠炎（UC）的自身免疫性很可能是可疑的。 我们建议：目标1.）利用发现额外的IBD风险基因座；改进我们的信息学， 包括等位基因特定分析；以及积累的新染色质免疫沉淀数据重新定义 协会以前发现（1）。目标2.）更好地了解IBD的基因组机制 最先进的基因组技术。目标3.）开发针对EBV的IBD的新疗法， 特别是针对EBV的延迟III转换表达程序，目标4.）测试预测 IBD中EBV感染增加的病因可能性，如果是的话，请确定的特征 IBD子集与IBD的炎症病理学有关，也许是患有自身免疫UC的病理学。 该项目将确定EBV是否是某些IBD的合理病因，是调节基因组的特征 风险基因座的机制，并启动实验以找到新的疗法，以减少EBV对IBD的影响。