循环代谢物与肝细胞癌风险的孟德尔 随机化研究

A Mendelian Randomization Study on the Association between Circulating Metabolites and the Risk of Hepatocellular Carcinoma

摘要: 背景：代谢重编程是肝癌发生发展的重要特征，但循环代谢物与肝细胞癌(hepatocellular carcinoma, HCC)风险之间的因果关系尚不明确。本研究旨在系统评估233种循环代谢物与HCC风险之间的潜在因果关联。方法：本研究采用双样本孟德尔随机化(Mendelian randomization, MR)设计，主要分析方法为逆方差加权法(inverse-variance weighted, IVW)。代谢物的遗传工具变量来源于一项大规模全基因组关联研究(genome-wide association study, GWAS)，HCC结局数据来自FinnGen联盟第9版数据。结果：通过IVW分析以及异质性和水平多效性检验，共识别出3种与HCC风险存在显著因果关联的代谢物。其中，白蛋白水平(OR = 1.8931, P = 0.0375)和乳酸水平(OR = 3.2161, P = 0.0153)与HCC风险呈正相关，而丙酮水平(OR = 0.3349, P = 0.0135)与HCC风险呈负相关。敏感性分析未检测到显著的水平多效性或异质性(P > 0.05)。结论：本研究为循环代谢物与HCC风险之间的因果关联提供了遗传学证据，鉴定出3种具有潜在相关性的代谢物，为HCC的早期风险识别及机制探索提供了新的线索。

Abstract: Background: Metabolic reprogramming is a hallmark of hepatocarcinogenesis, but the causal relationships between circulating metabolites and the risk of hepatocellular carcinoma (HCC) remain unclear. This study aimed to systematically evaluate the potential causal associations between 233 circulating metabolites and HCC risk. Methods: A two-sample Mendelian randomization (MR) design was employed, with inverse-variance weighted (IVW) as the primary analysis method. Genetic instruments for metabolites were derived from a large-scale genome-wide association study (GWAS), and HCC outcome data were obtained from the FinnGen consortium (release 9). Results: Through IVW analysis combined with heterogeneity and horizontal pleiotropy tests, three metabolites were identified to have significant causal associations with HCC risk. Albumin (OR = 1.8931, P = 0.0375) and lactate (OR = 3.2161, P = 0.0153) were positively associated with HCC risk, while acetone (OR = 0.3349, P = 0.0135) was negatively associated with HCC risk. Sensitivity analyses detected no significant horizontal pleiotropy or heterogeneity (P > 0.05). Conclusion: This study provides genetic evidence for causal associations between circulating metabolites and HCC risk, identifying three potentially relevant metabolites that offer new clues for early risk identification and mechanistic investigation of HCC.