Exposome and Precision Medicine in NAFLD

非酒精性脂肪肝（NAFLD）是最常见的肝脏疾病，通常与肥胖有关 和代谢紊乱。 NAFLD 的临床病程各不相同，只有部分患者发展为非酒精性脂肪肝 脂肪性肝炎（NASH）和进行性纤维化会增加死亡率。对环境的贡献 NAFLD 先前已通过特殊暴露队列研究和动物模型得到证实。然而， 数据差距阻碍了这一新兴环境健康科学知识的临床应用，从而影响 通过精准医学方法对 NAFLD 患者进行临床护理。该项目提出了一种新的、高 影响力，虚拟联盟（NAFLD-ViCTER）进行协同，多学科，转化 对成人 NAFLD 患者进行暴露组学研究，以解决这些知识差距。它检验了以下假设： 环境暴露会影响 NAFLD 的严重程度、自然病程以及对肝脏治疗的反应 转录重编程导致代谢紊乱。该财团由调查人员组成 拥有来自三个中心的协同专业知识和资源，包括：Matt Cave（路易斯维尔大学 PI）、 Naga Chalasani（Co-I，印第安纳大学）和 Dean Jones（Co-I，埃默里大学）。具体目标是：1） 在横断面研究中确定与成人 NAFLD 严重程度相关的环境暴露。这个 具有内部比较的分析横断面研究利用之前收集、存档、去识别化的资料 来自成年 NAFLD 患者的材料，其特征在于振动控制瞬态弹性成像和 组织学。非靶向高分辨率暴露组学 (HRE) 将在血浆中进行。性别差异将会 调查了。将进行全暴露组关联研究 (EWAS) 与 NAFLD 严重程度生物标志物的比较。 2） 阐明环境暴露增加 NAFLD 严重程度的机制。本次分析的 横断面研究利用目标 1 的材料以及先前确定的基因分型和肝脏 mRNA-SEQ 数据。非靶向高分辨率代谢组学 (HRM) 将在血浆中进行。 MWAS 和 将针对 (i) NAFLD 严重程度生物标志物和 (ii) 进行转录组广泛关联研究 (TWAS) 使用数据驱动的综合和路径分析与 NAFLD 严重程度相关的暴露。基因： 将检查环境相互作用。 3) 确定与NASH相关的环境化学物质 纵向研究中的组织学进展和治疗反应。存档的去识别化数据和血浆 标本来自先前发表的成人奥贝胆酸多中心安慰剂对照临床试验 NASH 将被利用。将进行血浆 HRE/HRM 以及相关的暴露/代谢特征 NASH 的组织学进展和治疗反应将使用安慰剂和奥贝胆碱来确定 酸治疗的患者，分别。 NAFLD-ViCTER 将改变对环境的临床理解 对 NAFLD 的贡献。它将为 NAFLD 中结合暴露组学的精准医学铺平道路。

Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease, and it is often associated with obesity and metabolic disruption. NAFLD has a variable clinical course, and only some patients develop nonalcoholic steatohepatitis (NASH) and progressive fibrosis which increase mortality. An environmental contribution to NAFLD has previously been demonstrated by special exposure cohort studies and animal models. However, data gaps prevent the clinical application of this emerging environmental health scientific knowledge to impact the clinical care of NAFLD patients through a precision medicine approach. This project proposes a new, high- impact, virtual consortium (the NAFLD-ViCTER) to conduct synergistic, multidisciplinary, translational exposomics research in adult NAFLD patients to address these knowledge gaps. It tests the hypothesis that environmental exposures contribute to NAFLD severity, natural history and response to therapy via hepatic transcriptional reprogramming resulting in metabolic disruption. The consortium is composed of investigators with synergistic expertise and resources from three centers including: Matt Cave (PI, University of Louisville), Naga Chalasani (Co-I, Indiana University), and Dean Jones (Co-I, Emory University). The specific aims are: 1) To determine the environmental exposures associated with adult NAFLD severity in a cross-sectional study. This analytical cross-sectional study with internal comparisons utilizes previously collected, archived, de-identified materials from adult patients with NAFLD characterized by vibration-controlled transient elastography and histology. Untargeted high-resolution exposomics (HRE) will be performed in plasma. Sex differences will be investigated. Exposome-wide association studies (EWAS) vs. NAFLD severity biomarkers will be performed. 2) To elucidate the mechanisms by which environmental exposures increase the severity of NAFLD. This analytical cross-sectional study utilizes materials from Aim 1 along with previously determined genotyping and hepatic mRNA-SEQ data. Untargeted high-resolution metabolomics (HRM) will be performed in plasma. MWAS and transcriptome wide association studies (TWAS) will be performed vs. (i) NAFLD severity biomarkers and (ii) the exposures associated with NAFLD severity using data-driven integrative and pathway analyses. Gene: environment interactions will be examined. 3) To determine the environmental chemicals associated with NASH histologic progression and response to therapy in a longitudinal study. Archived de-identified data and plasma specimens from a previously-published, multi-center, placebo-controlled clinical trial of obeticholic acid for adult NASH will be utilized. Plasma HRE/HRM will be performed and the exposures/metabolic signatures associated with NASH histologic progression and response to therapy will be determined using the placebo and obeticholic acid treated patients, respectively. NAFLD-ViCTER will transform the clinical understanding of the environmental contribution to NAFLD. It will pave the way for precision medicine incorporating exposomics in NAFLD.