炎症与胰岛素相关膳食模式及其代谢组学标志物与肝癌发生关系的前瞻性研究

我国是肝癌大国，饮食可作为癌症预防的重要手段，但饮食与肝癌的流行病学研究较少且相关机制尚不清楚。现有研究仅聚焦于单个食物与营养素，缺乏整个膳食模式的人群证据。申请人前期研究提示可修饰炎症与胰岛素抵抗的膳食因素与肝癌的发生有关。我们据此推测饮食可部分通过影响炎症与胰岛素等相关机制通路来影响肝癌的发生。本项目利用前瞻性队列，融合机制通路相关生物标志物与个体膳食数据，构建与炎症、促胰岛素分泌及胰岛素抵抗相关的膳食模式，并研究这些新颖的以验证机制学假设为目的的膳食模式与肝癌发生的关系；其次，为克服传统膳食调查的弊端，利用高通量代谢组学技术构建上述膳食模式的血清代谢物特征谱作为内暴露标志物，开展膳食模式内暴露标志物与肝癌发生关系的巢式病例—对照研究；最后，采用生信分析系统研究代谢物所代表的主要机制通路在肝癌发生中的贡献。预期结果可为肝癌的一级预防提供依据，并进一步揭示饮食影响肝癌发生的潜在机制。

Liver cancer is a common cancer with poor prognosis in China, thereby making primary prevention a key priority. Although modification of dietary habits shows a promising approach for cancer prevention, epidemiological research of association between diet and risk of developing liver cancer is limited and still in its infancy. Inflammation and insulin resistance/hyperinsulinemia are important pathways in hepatocarcinogenesis. Diets can modulate inflammation and insulin response. Therefore, we hypothesize that diet may influence liver cancer development through modulation of inflammatory and insulinemic pathways. To test this hypothesis, we will first develop and validate an empirical food-based dietary inflammatory index (EDII) and empirical dietary patterns for insulin resistance (EDIR) and hyperinsulinemia (EDIH) to assess the long-term inflammatory and insulinemic potential of usual diet in a subset within a community-based cohort. We then investigate the association of these 3 dietary patterns with the risk of liver cancer in the full cohort. Second, we will further derive plasma metabolomic signatures reflecting adherence to each dietary pattern using a novel high-throughput metabolomics approach. The association of these signatures, as an unbiased internal exposure of diet, with the risk of developing liver cancer, will be then evaluated in a nested case-control study. Last, to determine the underlying mechanisms between diet and liver cancer development, we will also evaluate how much the associations are mediated through dietary pattern-related metabolites using pathway analysis and mediation analysis. Findings from this application are expected to inform the primary prevention strategies for liver cancer and reveal the biological mechanisms by which diets may influence liver cancer occurrence.