Integrative multi-omic risk assessment at diagnosis and during disease progression in African-Americans with Inflammatory bowel disease

非洲裔美国人炎症性肠病诊断和疾病进展期间的综合多组学风险评估

• 批准号: 10543004
• 负责人: SUBRA KUGATHASAN
• 金额: $ 58.84万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-30 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10543004
• 关键词: Address; Affect; African; African American population; African ancestry; Alcohol consumption; Area; Automobile Driving; Biopsy; Body mass index; Butyrates; Cell physiology; Collection; Consent; Crohn' s disease; DNA; DNA Methylation; Data; Development; Diagnosis; Diet; Discipline; Disease; Disease Outcome; Disease Progression; Environment; Environmental Risk Factor; Epigenetic Process; Epithelial; Epithelial Cells; Ethnic Origin; European; Fibroblasts; Funding; Gene Expression; Gene Frequency; Genetic; Genetic Research; Genomic DNA; Genomics; Histologic; Human; Immune; Individual; Inflammatory; Inflammatory Bowel Diseases; Intestines; Investigation; Life Style; Light; Mediator of activation protein; Mendelian randomization; Metabolic; Methods; Methylation; Mucous Membrane; Online Systems; Onset of illness; Organoids; Outcome; Pathway interactions; Patient Recruitments; Patients; Plant Roots; Publishing; Rectum; Research; Resources; Risk; Risk Assessment; Role; Rural; Salivary; Sample Size; Sampling; Severities; Severity of illness; Smoking; TNF gene; Testing; Therapeutic; Time; Underrepresented Populations; Up-Regulation; Validation; Weight; adverse outcome; bead chip; cohort; combinatorial; community engagement; epigenome; experience; follow-up; gene discovery; genetic architecture; gut dysbiosis; gut microbiome; health disparity; ileum; immune function; indexing; innovation; insight; metabolic profile; metabolome; metabolomics; methylation pattern; microbial; microbiome; multiple omics; polygenic risk score; programs; recruit; rectal; research study; response; single-cell RNA sequencing

Summary Inflammatory bowel disease (IBD) in African Americans (AA) is likely to progress towards complicated disease and debilitating outcomes. These outcomes are likely rooted in genetic, epigenetic, microbial, and metabolic factors. We have made substantial advances in this research area, and over the past two funding cycles as Ancillary contributors to the IBD-GC produced sufficient outcomes to drive new studies, and here propose a focused set of three aims building on those advances. (1) Differences in allele frequency and effect size substantially impact polygenic risk assessment, (2) Gene expression in the ileum of AA IBD patients tends to display significant up-regulation of markers associated with adverse disease progression, including TNF response. (3) Genomic DNA methylation patterns in the rectum of IBD patients is maintained, reflecting the dominance of epithelial contributions over transient inflammatory signatures from the immune compartment. (4) AA tend to have a reduced mucosal fibroblast component relative to European cases. (5) Polygenic risk scores (PRS) for IBD are substantially modified by diet, smoking and alcohol consumption, but these factors have not been evaluated in AA despite substantial cultural differences. (6) IBD is associated with changes in the gut microbiome and differs by ethnicity and urban/rural lifestyle, suggesting a butyrate-induced modulation of epithelial and immune function. (7) We can experimentally evaluate the impact of genetic and metabolic perturbations on cellular function using patient biopsy derived organoids. Taken together, these insights have led to the overarching hypothesis that environmental factors modulate the epigenome and microbiome, driving adverse health disparity in AA with IBD. To test this, we propose the following three Specific Aims. For Aim 1, we will define the genetic architecture of IBD in AA by expanding the IBD-GC sampling, developing an inception cohort, and evaluating PRS×Environment interactions. In Aim 2, we will test the hypothesis that a subset of ileo-colonic methylation signatures are consistent with a role in IBD onset and/or severity, rather than an outcome of IBD, and determine whether these signatures are independent of, or interacting with, the environmental factors of Aim 1. Finally, in Aim 3, we will use ileo-colonic biopsies and enteroid cultures to test the hypothesis that differences in the microbiome drive metabolic profiles that associate with gut dysbiosis in IBD. Together, our multi-omic approach and breadth of expertise across multiple disciplines will shed new light on disease outcomes of IBD related to differences in the genomics and metabolomics of AA ancestries.

概括 非洲裔美国人（AA）的炎症性肠病（IBD）可能会进展 复杂的疾病和衰弱的结果。这些结果可能源于遗传， 表观遗传，微生物和代谢因子。我们在这项研究中取得了重大进步 在过去的两个资金周期中，作为IBD-GC产生的辅助贡献者 足够的结果来推动新研究，在这里提出了一个集中的三个目标建设的集合 关于这些进步。 （1）等位基因频率和效应大小的差异显着影响 多基因风险评估，（2）AA IBD患者回肠中的基因表达倾向于显示 与不良疾病进展相关的标记的显着上调，包括TNF 回复。 （3）维持IBD患者直肠的基因组DNA甲基化模式，维持 反映上皮贡献的优势对瞬态炎症特征的优势 免疫室。 （4）AA倾向于减少粘膜成纤维细胞成分 欧洲案件。 （5）IBD的多基因风险评分（PR）通过饮食大大改变， 吸烟和饮酒，但在AA需求中尚未评估这些因素 实质性文化差异。 （6）IBD与肠道微生物组的变化有关 种族和城市/农村生活方式的差异，表明对上皮的调节 和免疫功能。 （7）我们可以通过实验评估遗传和代谢的影响 使用患者活检衍生的类器官对细胞功能的扰动。总的来说，这些 见解导致了总体假设，即环境因素调节 表观基因组和微生物组，带有IBD的AA不良健康差异。为了测试这一点，我们 提案以下三个特定目标。对于AIM 1，我们将定义 IBD在AA中通过扩展IBD-GC采样，开发成立队列并评估 PRS×环境相互作用。在AIM 2中，我们将检验以下假设：Ileo-Colonic的子集 甲基化特征与在IBD发作和/或严重性中的作用一致，而不是 IBD的结果，并确定这些签名是独立于或与之互动的 目标1的环境因素。最后，在AIM 3中，我们将使用Ileo-Colonic活检和肠内 培养以检验以下假设：微生物组驱动代谢谱的差异 与IBD中的肠道营养不良。共同，我们的多运动方法和专业知识广度 在多个学科中 在AA祖先的基因组学和代谢组学中。