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

总结 非裔美国人（AA）的炎症性肠病（IBD）可能进展为 复杂的疾病和衰弱的结果。这些结果很可能源于基因， 表观遗传、微生物和代谢因素。我们在这项研究中取得了实质性的进展 在过去的两个资助周期中，作为IBD-GC的辅助贡献者， 足够的结果来推动新的研究，并在这里提出了一套重点的三个目标建设 这些进步。(1)等位基因频率和效应量的差异 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志物显著上调，包括TNF 反应(3)IBD患者直肠中的基因组DNA甲基化模式得以维持， 这反映了上皮细胞的贡献超过了短暂的炎症信号， 免疫区室(4)AA倾向于减少粘膜成纤维细胞成分， 欧洲案例。(5)IBD的多基因风险评分（PRS）通过饮食显著改变， 吸烟和饮酒，但这些因素尚未在AA中进行评估， 实质性的文化差异。(6)IBD与肠道微生物组的变化相关， 不同的种族和城市/农村的生活方式，表明丁酸诱导的调节上皮细胞 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干扰细胞功能。综上所述各项 洞察力导致了总体假设，即环境因素调节 表观基因组和微生物组，推动AA与IBD的不利健康差异。为了验证这个，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采样，开发初始队列，并评估 PRS×环境交互作用。在目标2中，我们将检验以下假设： 甲基化特征与IBD发作和/或严重性中的作用一致，而不是与IBD的发病和/或严重性相关。 IBD的结果，并确定这些签名是否独立于，或相互作用， 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小肠活检。 培养来检验微生物组的差异驱动代谢谱的假设， 与IBD中的肠道生态失调有关。我们的多组学方法和广泛的专业知识 跨多个学科的研究将为IBD的疾病结局提供新的线索， 基因组学和代谢组学的研究。

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.