Proposing an Optimized Prediction Model for Pancreatic Cancer Based on Mendelian Randomization Analysis of Fibrinogen Levels and Urinary Protein Excretion Rate.

[BACKGROUND] An ongoing debate exists on the relationship between fibrinogen levels, urinary albumin excretion (UAE), and pancreatic ductal adenocarcinoma (PDAC), as demonstrated by clinical data of patients with benign and malignant pancreatic tumors.

[METHODS] FinnGen and EMBL-EBI provided data on single-nucleotide polymorphisms associated with fibrinogen levels, UAE, and PDAC. To examine exposure-outcome relationships, weighted median, MR-Egger, and inverse variance weighted methods were employed. Heterogeneity and horizontal pleiotropy were evaluated using Cochran's Q test and MR-Egger intercept analysis, respectively. The robustness of the Mendelian randomization (MR) analysis results was assessed using a leave-one-out sensitivity analysis. Clinical information, including sex, age, tumor location, pathological diagnosis, UAE level, fibrinogen level, and serum carbohydrate antigen 19-9 (CA19-9) level, was collected from patients with pancreatic malignant tumors at Peking Union Medical College Hospital from 2019 to 2024.

[RESULTS] Fibrinogen levels and PDAC exhibited a strong positive causal association according to MR analysis (95% confidence interval [CI]: 1.630 to 8.753;  = .004). The UAE and PDAC exhibited a substantial beneficial causal association (95% CI: 0.055 to 3.831;  = .044) in the intercept analysis, and Cochran's Q test did not show horizontal pleiotropy or heterogeneity ( > .05). Sensitivity analysis demonstrated the robustness of the findings. The inclusion of both fibrinogen and UAE levels increased the prediction rate for pancreatic malignancy by 6.36%. Genetic variations at SLC22A4 (rs12777) and FMO4 (rs1227104) may influence systemic inflammation, fibrinogen production, renal/metabolic homeostasis, and immunometabolic reprogramming, thereby shaping the tumor microenvironment and contributing to PDAC development.

[CONCLUSION] This study demonstrated the potential of fibrinogen levels and UAE as biomarkers of pancreatic malignancy through MR and clinical data validation. These metrics significantly improved the prediction of pancreatic cancer when used in combination with CA19-9 levels. In addition, this study proposes a mechanism for fibrinogen levels and UAE in PDAC involving SLC22A4 and FMO4.