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.

对非常早期发作炎症性肠病（VEO-IBD）或IBD的发展的基因组贡献 在<6岁时被诊断出来，仍然被了解，但阐明遗传危险因素无疑会 增强我们对发病机理的理解，并提出新颖的治疗方法。 VEO-IBD患者 通常比较老的IBD更有疾病的程度和严重程度。传统疗法 免疫抑制常常失败，在免疫缺陷的情况下，是不合适的。侵略性 表型，早期发作和强大的家族史表明，素质缺陷富集了veo-ibd。 实际上，我们和其他人已经确定了素食 - IBD中的因果遗传变异。整个外显子组测序（WES）具有 从根本上改变了我们对veo-ibd的方法。但是，将确定的变体与开发联系起来 VEO-IBD表型仍然很困难。该提议的目的是扩大高度渗透物的曲目， 通过对良好表征患者的大规模测序研究负责VEO-IBD的因果变异 队列，然后在独立队列中复制以及对某些已识别变体的功能验证。 我们的核心假设是，单个基因缺陷负责大部分患有vEO-ibd的病例， 它们可以有效地以从最新基因组开始的多学科方法来表征 研究。此外，我们将测试确定的vEO-IBD基因和途径是否特定于早期发作 案例或还参与了更常见的旧发作IBD形式的敏感性。最后，我们会的 特别检验的假设是，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其在veo-ibd中的作用。迅速增加 VEO-IBD的发病率不能仅通过遗传易感性来解释，并提出了肠道的作用 微生物群是疾病的驱动力。为了检验我们的中心假设，在特定目的1中，我们将创建一个数据集 WES中VEO-IBD患者的潜在因果突变。我们在veo-ibd中使用WES的初步数据具有 已经确定了因果变异，证实了素质性缺陷在veo-ibd中的富集。我们现在会 增加样本量，以创建大量的候选基因目录，我们将在附加中验证 独立的VEO-IBD病例，并测试与较旧的IBD相关性。在特定的目标2中，候选人veo- IBD变体将受到功能研究的约束，以确认其因果关系。最后，在特定的目标3中，我们将 相关的数据从我们的平行研究“ veo-ibd中的微生物组”与目标1的基因组数据与 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鉴定出新的遗传原因，从而提供肥沃 购买的生物学过程来源，以更好地了解疾病的基本机制，最终 通过个体化和 靶向疗法。