An integrative approach to understanding the genetic basis of very early onset inflammatory bowel disease

基因组在极早发型炎症性肠病(VEO-IBD)发生发展中的作用 在6岁时被诊断出来，目前仍未得到研究，但阐明遗传风险因素无疑将是 提高我们对发病机制的理解，并提出新的治疗方法。VEO-IBD患者 通常比起病较早的IBD具有更大的疾病范围和严重程度。传统疗法与 免疫抑制通常失败，在免疫缺陷的情况下，免疫抑制是不合适的。咄咄逼人的 表型、早期发病和强烈的家族史表明VEO-IBD的单基因缺陷较多。 事实上，我们和其他人已经确定了VEO-IBD的因果遗传变异。全外显子组测序(WES) 彻底改变了我们对VEO-IBD的治疗方法。然而，将WES确定的变体与开发 VEO-IBD的表型仍然很困难。这项提议的目标是扩大高渗透性的曲目， 通过对一名特征良好的患者进行大规模测序研究，发现与VEO-IBD相关的因果变异 随后，在独立的队列中进行复制，并对一些已确定的变体进行功能验证。 我们的中心假设是，单一基因缺陷导致了很大比例的VEO-IBD病例， 从最先进的基因组学出发，多学科的方法可以有效地描述它们的特征 学习。此外，我们将测试已识别的VEO-IBD基因和途径是否针对早发性 病例或也与更常见的较常见的老年IBD易感性有关。最后，我们会 具体测试假设，特定基因和途径中的因果变异将与 肠道微生物群组成的变化将支持它们在VEO-IBD中的作用。快速增长的 VEO-IBD的发生不能仅用遗传易感性来解释，这表明肠道的作用 微生物区系是疾病的驱动力。为了测试我们的中心假设，在特定目标1中，我们将创建一个数据集 用WES分析VEO-IBD患者潜在的致病突变。我们在VEO-IBD中使用WES的初步数据 已经确定的因果变异证实了VEO-IBD中单基因缺陷的丰富。我们现在就会 增加我们的样本量以创建大量候选基因目录，我们将在其他 独立的VEO-IBD病例，并测试与较早发病的IBD的相关性。在具体目标2中，候选人VEO- IBD的变种将接受功能研究，以确认它们的因果效应。最后，在具体目标3中，我们将 将我们平行研究“VEO-IBD中的微生物组”获得的数据与AIM 1的基因组数据相关联 寻找与导致VEO-IBD的不同途径的缺陷相关的微生物区系的变化。 该项目的完成将导致确定VEO-IBD的新遗传原因，为 追求源头生物过程，以更好地了解疾病的基本机制，具有终极意义 将这些知识转化为改善对VEO-IBD儿童的护理的目标是通过个性化和 靶向治疗。

The genomic contribution to the development of very early onset inflammatory bowel disease (VEO-IBD), or IBD diagnosed at <6 years of age, remains understudied, yet elucidation of genetic risk factors would undoubtedly enhance our understanding of pathogenesis and suggest novel therapeutic approaches. Patients with VEO-IBD often present with greater extent and severity of disease than older onset IBD. Traditional therapies with immunosuppression often fail and in cases of immune deficiencies, are inappropriate. The aggressive phenotype, early onset, and strong family history points to an enrichment of monogenic defects in VEO-IBD. Indeed, we and others have identified causal genetic variants in VEO-IBD. Whole exome sequencing (WES) has radically changed our approach to VEO-IBD. However, linking the WES identified variant to the development of the VEO-IBD phenotype remains difficult. The goal of this proposal is to expand the repertoire of highly penetrant, causal variants responsible for VEO-IBD through a large scale sequencing study of a well characterized patient cohort, followed by replication in independent cohorts and functional validation of some of the identified variants. Our central hypothesis is that single gene defects are responsible for a large proportion of cases with VEO-IBD, and they can be effectively characterized by a multidisciplinary approach starting from state-of-the-arts genomic studies. In addition, we will test whether the identified VEO-IBD genes and pathways are specific to early onset cases or are also involved in susceptibility to the more common form of older onset IBD. Finally, we will specifically test the hypothesis that causal variants in specific genes and pathways will be associated with changes in the gut microbiome composition that will support their role in VEO-IBD. The rapidly increasing incidence of VEO-IBD cannot be explained by genetic susceptibility alone, and suggests a role of the gut microbiota as a driver of disease. To test our central hypothesis, in Specific Aim 1 we will create a dataset of potential causal mutations in VEO-IBD patients by WES. Our preliminary data using WES in VEO-IBD has already identified causal variants confirming the enrichment of monogenic defects in VEO-IBD. We will now increase our sample size to create a large catalogue of candidate genes that we will validate in additional independent VEO-IBD cases, and test for association with older onset IBD. In Specific Aim 2, candidate VEO- IBD variants will be subject to functional studies to confirm their causal effects. Finally, in Specific Aim 3, we will correlate data obtained from our parallel study “The Microbiome in VEO-IBD” with the genomic data of Aim 1 to look for changes in the microbiota associated with the defects in the different pathways leading to VEO-IBD. Completion of this project will result in the identification of novel genetic causes of VEO-IBD, providing a fertile source of biologic processes to pursue to better understand the basic mechanisms of disease, with the ultimate goal of translating this knowledge into improved care for children with VEO-IBD through individualized and targeted therapy.