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

了解极早发炎症性肠病遗传基础的综合方法

• 批准号: 10005948
• 负责人: Judith Rachel Kelsen
• 金额: $ 25.7万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-15 至 2021-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10005948
• 关键词: 6 year old; Affect; Biological; Biological Process; Candidate Disease Gene; Catalogs; Cell physiology; Cells; Child; Child Care; Collaborations; Complex; Correlation Studies; Data; Data Set; Defect; Development; Diagnosis; Disease; Enterocytes; Environmental Impact; Family; Genes; Genetic; Genetic Predisposition to Disease; Genomics; Goals; Gut Mucosa; Immune; Immunosuppression; Immunosuppressive Agents; Incidence; Infant; Inflammatory Bowel Diseases; Knowledge; Large-Scale Sequencing; Link; Metagenomics; Morbidity - disease rate; Mucosal Immune System; Mutation; Pathogenesis; Pathway interactions; Patients; Phenotype; Population; Predisposition; Recording of previous events; Resources; Role; Sample Size; Secondary to; Severity of illness; Single-Gene Defect; Source; Testing; Translating; Validation; Variant; candidate validation; causal variant; cohort; data warehouse; disease diagnosis; disease phenotype; early onset; exome sequencing; genetic risk factor; genetic variant; genome wide association study; genomic data; gut microbiome; gut microbiota; improved; individualized medicine; insight; interdisciplinary approach; microbial; microbiome; microbiome composition; microbiome research; microbiota; new therapeutic target; novel; novel therapeutic intervention; personalized medicine; rare variant; risk variant; targeted treatment; traditional therapy

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.

基因组对极早发型炎症性肠病（VEO-IBD）或IBD发展的贡献 在<6岁时被诊断出来，仍然没有得到充分的研究，但遗传风险因素的阐明无疑将 增强我们对发病机制的了解并提出新的治疗方法。VEO-IBD患者 通常表现为比老年发病IBD更大的疾病范围和严重程度。传统疗法， 免疫抑制常常失败，且在免疫缺陷情况下是不合适的。咄咄逼人的 表型、早发和强家族史表明VEO-IBD中单基因缺陷的富集。 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） 从根本上改变了我们对VEO-IBD的方法。然而，将WES鉴定的变体与 VEO-IBD表型仍然是困难的。这项建议的目的是扩大高渗透性， 通过对充分表征的患者进行大规模测序研究，发现导致VEO-IBD的致病变体 队列，然后在独立队列中进行复制，并对一些鉴定的变体进行功能验证。 我们的中心假设是单基因缺陷是大部分VEO-IBD病例的原因， 它们可以通过多学科方法有效地表征， 问题研究此外，我们还将检测所鉴定的VEO-IBD基因和途径是否对早发性IBD具有特异性。 病例或也涉及对更常见形式的老年发病IBD的易感性。最后我们将 具体地测试假设，即特定基因和途径中的因果变异将与 肠道微生物组组成的变化将支持它们在VEO-IBD中的作用。迅速增加的 VEO-IBD的发病率不能单独用遗传易感性来解释，这表明肠道的作用。 微生物群是疾病的驱动力。为了检验我们的中心假设，在具体目标1中，我们将创建一个数据集， 通过WES检测VEO-IBD患者中的潜在致病突变。我们在VEO-IBD中使用WES的初步数据显示， 已经鉴定的致病变体证实了VEO-IBD中单基因缺陷的富集。我们现在将 增加我们的样本量，以创建一个大型的候选基因目录，我们将在其他 独立的VEO-IBD病例，并检测与老年发病IBD的相关性。在具体目标2中， IBD变体将进行功能研究，以确认其因果效应。在第三个目标中，我们将 将从我们的平行研究“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的不同途径中的缺陷相关的微生物群的变化。 该项目的完成将导致VEO-IBD的新遗传原因的鉴定， 生物过程的来源，以更好地了解疾病的基本机制，最终 我们的目标是通过个性化和个性化的方式， 靶向治疗