Proteomics identifies complement protein signatures in patients with primary biliary cholangitis

Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease lacking reliable biomarkers for diagnosis or prognosis. To identify plasma complement biomarkers that improve diagnosis and prognosis of PBC. We analyzed large-scale proteomic data from the UK Biobank, concentrating on complement components linked to PBC. A total of 44 PBC patients, including 13 baseline cases and 31 incident cases, were evaluated alongside matched controls based on demographic factors. Proteomic analysis revealed significantly elevated levels of complement proteins, including complement receptor 1 (CR1), complement component 1q subcomponent A chain (C1QA), complement component 1q subcomponent-like 2 (C1QL2), complement component 7 (C7), and component 9 (C9) in PBC patients (P < 0.05). Among these, C1QA, C1QL2, C7, and CR1 demonstrated strong diagnostic potential. Elevated levels of CR1, complement receptor 1 (CR2), C1QA, C1QL2, and C7 were linked to increased risk of PBC onset (P < 0.05). Further analysis revealed that CR1, CR2, C1q and tumor necrosis factor-related protein 1 (C1QTNF1), C1q and tumor necrosis factor-related protein 5 (C1QTNF5), and C7 were associated with more severe liver outcomes (P < 0.05), while lower levels of complement component 5 (C5) and complement C1r subcomponent-like protein (C1RL) correlated with worse outcomes (P = 0.002). Notably, CR1 had the highest predictive accuracy for adverse outcomes (AUC = 81.85), outperforming traditional liver fibrosis markers such as the Fibrosis-4 (FIB-4) index (AUC = 76.33). Complement components, particularly CR1, may serve as valuable biomarkers for diagnosing PBC and predicting its severity.