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. 2025 Jan;14(1):e70570.
doi: 10.1002/cam4.70570.

Assessing the Causal Effect of Circulating Protein-To-Protein Ratio on the Risk of Morbidity of Hepatocellular Carcinoma

Qiuyuan Yue  1   2 , Xiaoxia Li  3   4 , Xiaoye Wan  5 , Xi Lin  1 , Yueming Li  2 , Mingwei Zhang  3   4 , Shaohua Xu  6
Affiliations

Assessing the Causal Effect of Circulating Protein-To-Protein Ratio on the Risk of Morbidity of Hepatocellular Carcinoma

Qiuyuan Yue et al. Cancer Med. 2025 Jan.

Abstract

Objective: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Mendelian randomization; circulating proteins; hepatocellular carcinoma; protein‐to‐protein ratio.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Study workflow of the Mendelian randomization (MR) analysis.
FIGURE 2
FIGURE 2
Primary analysis of causal associations between protein–protein ratio and HCC pathogenesis using a FinnGen database.
FIGURE 3
FIGURE 3
Primary analysis of causal associations between protein–protein ratio and HCC pathogenesis using the IEU database.
FIGURE 4
FIGURE 4
TSMR results of individual proteins and HCC. TSMR, two‐sample Mendelian randomization.
FIGURE 5
FIGURE 5
MR results of single protein and drug‐target in HCC. MR, Mendelian randomization.
See this image and copyright information in PMC

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