Assessing the Causal Effect of Circulating Protein‐To‐Protein Ratio on the Risk of Morbidity of Hepatocellular Carcinoma
Qiuyuan Yue, Xiaoxia Li, Xiaoye Wan, Xi Lin, Yueming Li, Mingwei Zhang, Shaohua XuABSTRACT
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.