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 非裔美国人 (AA) 的炎症性肠病 (IBD) 可能会发展为 复杂的疾病和使人衰弱的结果可能根源于遗传、 我们在这项研究中取得了实质性进展。 领域，并在过去两个资助周期中作为 IBD-GC 的辅助捐助者产生 足够的成果来推动新的研究，并在此提出一组有针对性的三个目标 (1) 等位基因频率和效应大小的差异会产生重大影响。 多基因风险评估，（2）AA IBD患者回肠基因表达趋势显示 与不良疾病进展相关的标志物显着上调，包括 TNF (3) IBD患者直肠的基因组DNA甲基化模式得以维持， 反映了上皮细胞对短暂炎症特征的主导作用 (4) AA 的粘膜成纤维细胞成分相对较少 (5) IBD 的多基因风险评分 (PRS) 因饮食而发生显着改变， 吸烟和饮酒，但这些因素尚未在 AA 中进行评估，尽管 (6) IBD与肠道微生物组的变化有关 因种族和城乡生活方式而异，表明丁酸诱导的上皮细胞调节 (7)我们可以通过实验评估遗传和代谢的影响。 总而言之，使用患者活检衍生的类器官对细胞功能进行干扰。 深入的见解得出了一个总体假设：环境因素调节 表观基因组和微生物组，导致 AA 与 IBD 的不良健康差异。 提出以下三个具体目标 对于目标 1，我们将定义 的遗传架构。 AA 中的 IBD 通过扩大 IBD-GC 抽样、开发初始队列并评估 PRS×环境相互作用在目标 2 中，我们将检验回结肠子集的假设。 甲基化特征与 IBD 发病和/或严重程度的作用一致，而不是与 IBD 发病和/或严重程度一致。 IBD 的结果，并确定这些特征是否独立于或与之相互作用 目标 1 的环境因素。最后，在目标 3 中，我们将使用回结肠活检和肠样 培养物来检验微生物组差异驱动代谢特征的假设 我们的多组学方法和广泛的专业知识与 IBD 肠道菌群失调有关。 跨多个学科将为研究与差异相关的 IBD 疾病结果提供新的线索 AA 血统的基因组学和代谢组学。