全暴露组关联研究（EWAS）新方法及其在肝癌风险因子发现中的应用

环境暴露与人类健康密切相关。全暴露组关联研究（exposome-wide association study-EWAS）可通过测定生物基质中外源及内源性化合物的变化阐明环境暴露与健康效应的关系。如何实现不同丰度的外源及内源性化合物的同时分析和信息提取是当前全暴露组关联研究所面临的巨大挑战。本项目围绕环境暴露与健康危害的重大科学问题，利用课题组多年来在代谢组学研究方面的学术积累，构建基于多维色谱-高分辨质谱的高覆盖度、高灵敏度的暴露组学分析平台，以提高色谱峰容量，实现外源及内源性化合物的同时分析和信息最大化，结合“计算暴露组学”数据挖掘手段和未知物鉴定策略，实现不同丰度内暴露组和代谢组的信息提取及规模化定性，尤其是低丰度信号的提取和注释。在此基础上将所建方法用于肝癌巢式队列人群血清的暴露组学研究，筛选肝癌风险因子及预警标志物，为肝癌的早期诊断及预防提供依据。

Environmental exposure is closely related to human health. Exposome-wide association study (EWAS) is a promising tool to elucidate the relationship between environmental exposure and health by measuring the significant changes of exogenous and endogenous compounds in biological matrix. However, the challenge in EWAS is to realize full coverage and maximized structural annotation of exogenous and endogenous compounds in a large concentration range. Therefore, in this project, novel analytical methods with high coverage, high sensitivity are to be developed based on multi-dimensional liquid chromatography system coupled with high resolution mass spectrometry, which aims to improve peak capacity and maximize the information acquisition of exogenous and endogenous compounds. Furthermore, computational exposomics is applied to extract signals with low abundance, and a new compound identification strategy based on molecular networking, quatitative structure-(chromatographic) retention relationships (QSRR), modulated modularity clustering analysis (MMC) and home-made database is established to improve efficiency and reliability of compounds identification. Finally, the developed method is applied to screen and validate the risk factors and prospective early-warning marker(s) of hepatocellular carcinoma (HCC) in the nested cohorts, which provides not only new insight to the etiological study of HCC, but also evidence for the early diagnosis and prevention of HCC.