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

摘要 非裔美国人(AA)的炎症性肠病(IBD)可能进展为 复杂的疾病和令人衰弱的结果。这些结果很可能根植于基因， 表观遗传、微生物和代谢因素。我们在这项研究上取得了实质性进展。 在过去的两个供资周期中，作为IBD-GC的辅助捐助者产生了 足够的结果来推动新的研究，并在这里提出一套有重点的三个目标的建立 在这些进展上。(1)等位基因频率和效应大小的差异显著影响 多基因风险评估，(2)再生障碍性肠病患者回肠基因表达倾向于 显著上调与不良疾病进展相关的标记物，包括肿瘤坏死因子 回应。(3)IBD患者直肠基因组DNA甲基化模式保持不变， 反映了上皮成分对暂时性炎症信号的主导作用 免疫隔间。(4)再生障碍性贫血的粘膜成纤维细胞成分相对减少 到欧洲的案子。(5)IBD的多基因风险评分(PR)显著受饮食的影响， 吸烟和饮酒，但这些因素在再生障碍性贫血中尚未得到评估，尽管 巨大的文化差异。(6)IBD与肠道微生物群的变化有关， 不同的种族和城乡生活方式，表明丁酸诱导的上皮细胞的调节 和免疫功能。(7)我们可以从实验上评估遗传和代谢的影响 使用患者活检衍生的有机化合物对细胞功能的扰动。这些加在一起， 洞察力导致了一个重要的假设，即环境因素调节了 表观基因组和微生物组，导致再生障碍性贫血和炎症性肠病的不良健康差异。为了测试这一点，我们 提出以下三个具体目标。对于目标1，我们将定义 通过扩大IBD-GC样本，开发初始队列，并评估 PRS×环境交互作用。在目标2中，我们将检验回肠-结肠的一个子集 甲基化特征与IBD发病和/或严重程度的作用一致，而不是 IBD的转归，并确定这些信号是否独立于或与 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，以测试微生物组的差异驱动代谢特征的假设 与IBD的肠道生物失调有关。总而言之，我们的多元化方法和专业知识广度 跨多个学科将为IBD与差异相关的疾病结局提供新的线索 在AA祖先的基因组学和代谢组学中。

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.