肥胖是一个全球性的健康问题，也是包括肝细胞癌 (HCC) 在内的癌症的独立危险因素。然而，关于肥胖与肝癌之间因果关系的证据有限且尚无定论。本研究旨在调查肥胖相关特征与 HCC 风险之间的因果关系，并利用生物信息学方法探讨潜在机制。利用公开的关于肥胖特征（体重指数、体脂百分比、腰围、腰臀比、内脏脂肪组织体积）和 HCC 的全基因组关联研究汇总数据进行两样本孟德尔随机化分析。研究了肥胖与主要机制（胰岛素抵抗、脂肪因子、炎症）的关联及其对 HCC 的影响。鉴定了肥胖和肝癌中的差异表达基因并进行了功能富集分析。分析了与肿瘤微环境（TME）和免疫治疗标志物的相关性。基因预测的较高体重指数和体脂百分比与 HCC 风险增加存在显着因果关系。总体肥胖还与胰岛素抵抗、循环瘦素水平、C反应蛋白水平和严重胰岛素抵抗2型糖尿病的风险存在因果关系。四种差异表达基因（ESR1、GCDH、FAHD2A、DCXR）在肥胖和肝癌中常见。富集分析表明它们在 RNA 加帽、病毒转录、IL-17 信号传导和内分泌抵抗等过程中的作用。它们与 HCC 中的免疫细胞浸润和免疫治疗标志物呈负相关。总体肥胖可能通过影响主要机制对欧洲人的肝癌风险产生因果影响。所鉴定的差异表达基因可能通过调节细胞周期、炎症和免疫逃避与肥胖诱导的肝癌发生有关。有必要对精确机制进行进一步研究。© 2024。作者。

Obesity is a global health concern and independent risk factor for cancers including hepatocellular carcinoma (HCC). However, evidence on the causal links between obesity and HCC is limited and inconclusive. This study aimed to investigate the causal relationship between obesity-related traits and HCC risk and explore underlying mechanisms using bioinformatics approaches. Two-sample Mendelian randomization analysis was conducted leveraging publicly available genome-wide association study summary data on obesity traits (body mass index, body fat percentage, waist circumference, waist-to-hip ratio, visceral adipose tissue volume) and HCC. Associations of obesity with primary mechanisms (insulin resistance, adipokines, inflammation) and their effects on HCC were examined. Differentially expressed genes in obesity and HCC were identified and functional enrichment analyses were performed. Correlations with tumor microenvironment (TME) and immunotherapy markers were analyzed. Genetically predicted higher body mass index and body fat percentage showed significant causal relationships with increased HCC risk. Overall obesity also demonstrated causal links with insulin resistance, circulating leptin levels, C-reactive protein levels and risk of severe insulin resistant type 2 diabetes. Four differentially expressed genes (ESR1, GCDH, FAHD2A, DCXR) were common in obesity and HCC. Enrichment analyses indicated their roles in processes like RNA capping, viral transcription, IL-17 signaling and endocrine resistance. They exhibited negative correlations with immune cell infiltration and immunotherapy markers in HCC. Overall obesity likely has a causal effect on HCC risk in Europeans, possibly via influencing primary mechanisms. The identified differentially expressed genes may be implicated in obesity-induced hepatocarcinogenesis through regulating cell cycle, inflammation and immune evasion. Further research on precise mechanisms is warranted.© 2024. The Author(s).