Genomics of Inflammatory Bowel Disease

在炎症性肠病(EBV)中，EB病毒(EBV)的感染被认为与疾病有关 严重程度和对治疗的抗拒。最近，我们发现DNA和DNA之间有很强的关联 EBNA2和IBD危险基因座的免疫沉淀，与112个评估基因座中的38个相交(来自GWAS 2015年目录)(RR=3.3，Pc=1.24x10-13)(1)。较新的数据证实了EBNA2的关联，也表明 EBNA3C和EBNALP CHIP-SEQ(染色质免疫沉淀与下一代测序)数据是 与IBD基因座(RR=2.3，Pc=2.3x10-12；RR=2.3，Pc=2.3x10-12)有关； 与EBV裂解程序转录因子(Tf)无关。表达了EBNA2、EBNA3C和EBNALP 在EBV潜伏期III程序的病毒基因表达，导致感染的B细胞转化和成为 这是正常人类免疫系统不完全破坏的主要目标。有趣的是，人类 转录因子(TF)倾向于结合与这些潜伏期III EBV基因产物结合的相同基因座， 形成交叉簇，识别可能起作用的调控IBD基因座。我们的解释是 这些关联强烈地表明，在相交的基因座上，病毒机制侵占了 细胞表型与IBD风险的遗传机制是相同的。我们的结论是，这种关系很可能 代表相关的分子途径。问题是这些关联是否是相互关联的，反映了 汇聚但独立的机制，或者这些相关性是否相互依赖和存在，因为 该病毒是病原学的，并参与了疾病的发病机制。确定任何一种可能性都将是一个主要的 以病毒成分为探针剖析发病机制的IBD研究进展如果EBV感染是病原学的，那么， 也许，最初的EBV相关损害干扰了屏障功能，允许内源性微生物群 以诱导炎症反应，我们认为这是IBD的一种或多种病理机制。因为其他人 EBNA2相关疾病是自身免疫性疾病(1)，一些与IBD严重程度有关的EBV是结肠疾病，如果 EBV是病原学的，那么溃疡性结肠炎(UC)的自身免疫性是最有可能的怀疑对象。 我们建议：目标1。)利用其他IBD风险基因的发现；我们信息学的改进， 包括等位基因特异性分析；以及新的染色质免疫沉淀数据积累，以重新定义 以前发现的关联(%1)。目标2。)更好地理解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新疗法， 尤其是针对EBV的Latency III转化表达程序，以及Aim 4。)检验对……的预测 IBD中EBV感染增加的病因学可能性，如果是这样的话，那么确定 IBD亚群，其疾病与IBD的炎性病理有关，可能是患有自身免疫性UC的患者。 该项目将确定EBV是否是某些IBD的可信病因，表征调控基因组 研究风险基因的作用机制，并启动实验，寻找新的治疗方法，以减少EBV对IBD的影响。

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.