Yue Qiuyuan, Li Xiaoxia, Wan Xiaoye, Lin Xi, Li Yueming, Zhang Mingwei, Xu Shaohua
Department of Radiology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, Fujian, China.
Department of Radiology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China.
Cancer Med. 2025 Jan;14(1):e70570. doi: 10.1002/cam4.70570.
Several observational studies have identified an association between plasma proteins and hepatocellular carcinoma (HCC). This study aimed to explore the potential causal relationship between the circulating protein-to-protein ratio and the morbidity risk of HCC.
Genetic association data for circulating plasma proteins and 2821 protein-to-protein ratios were sourced from the UKB PPP and Suhre's study. Genetic association data for HCC were sourced from the FinnGen cohort (finngen-R11-HCC) and the IEU OpenGWAS project (ieu-b-4953). Subsequently, a two-sample Mendelian randomization (MR) and drug-targeted MR approach were used to evaluate causality associations. To bolster the robustness of our findings, we conducted a series of sensitivity analyses.
Eight protein-protein pairs were identified as causal factors for HCC in the two independent cohorts. For each standard deviation increase in protein-protein pair expression, susceptibility to HCC fluctuated from 0.4974 (95% confidence interval [CI]: 0.2506-0.9871) for the LAT2/SPRY2 protein pair to 1.9763 (95% CI: 1.3009-3.0026) for the ERBIN/LAT2 protein pair. However, among the significant protein pairs, only one circulating protein, TDRKH (odds ratio: 0.5964, 95% CI: 0.4196-0.8476), was causally associated with HCC.
Using multiple datasets and methods, eight protein-protein pairs were identified as having causal associations with HCC. Protein-protein interactions can provide meaningful findings beyond simple pQTL analysis.
多项观察性研究已确定血浆蛋白与肝细胞癌（HCC）之间存在关联。本研究旨在探讨循环蛋白与蛋白比值与HCC发病风险之间的潜在因果关系。
循环血浆蛋白和2821种蛋白与蛋白比值的基因关联数据来自英国生物银行血浆蛋白质组计划（UKB PPP）和苏雷的研究。HCC的基因关联数据来自芬兰基因队列（finngen-R11-HCC）和IEU OpenGWAS项目（ieu-b-4953）。随后，采用两样本孟德尔随机化（MR）和药物靶向MR方法来评估因果关联。为加强研究结果的稳健性，我们进行了一系列敏感性分析。
在两个独立队列中，确定了八对蛋白-蛋白对为HCC的因果因素。蛋白-蛋白对表达每增加一个标准差，HCC易感性波动范围为：LAT2/SPRY2蛋白对为0.4974（95%置信区间[CI]：0.2506 - 0.9871），ERBIN/LAT2蛋白对为1.9763（95%CI：1.3009 - 3.0026）。然而，在显著的蛋白对中，只有一种循环蛋白TDRKH（优势比：0.5964，95%CI：0.4196 - 0.8476）与HCC存在因果关联。
使用多个数据集和方法，确定了八对蛋白-蛋白对与HCC存在因果关联。蛋白-蛋白相互作用能提供超越简单蛋白质定量性状位点（pQTL）分析的有意义发现。
