Causal Association between Circulating Complement Components and Non-Viral Liver Diseases and Their Potential as Therapeutic Targets: An Integrated Analysis Based on Multi-omics Data

Abstract Backgrounds: To evaluate the causal correlation between complement components and non-viral liver diseases and their potential use as druggable targets. Methods Two-sample Mendelian randomization (MR) was performed to assess the causal effect of circulating complement components on the risk of several non-viral liver diseases. Then complement-based protein-protein interaction network was constructed to explore its involvement in the biological processes and network-based analysis of drug repositioning was conducted. Results In the MR analysis, genetically predicted levels of complement factor H-related protein 1 (CFHR1; OR: 0.621, p = 2.7*10 − 5 ) and H-related protein 2 (CFHR2; OR: 0.621, p = 2.7*10 − 5 ) were inversely associated with the risk of alcohol-related cirrhosis (ALC). Associations were significant between C8 gamma chain (C8G) and the risk of nonalcoholic fatty liver disease (NAFLD) (OR: 1.167, p = 0.011) and primary sclerosing cholangitis (PSC) (OR: 0.832, p = 0.027), C1QC chain (C1QC) and autoimmune hepatitis (AIH) (OR: 1.125, p = 0.021), and H-related protein 5 (CFHR5) and primary sclerosing cholangitis (PSC) (OR: 1.193, p = 0.007). Additionally, C1s (OR: 0.111, p = 0.017), C7 (OR: 1.631, p = 0.002), and CFHR2 (OR: 1.279, p = 0.011) were significantly associated with the risk of hepatocellular carcinoma. Protein-protein interaction network analysis showed that complement and complement-related proteins were widely enriched in liver disease-related biological functions. Potential drugs, including imatinib, thalidomide, verteporfin, atorvastatin, bortezomib, and calcitriol were highlighted for treating non-viral liver diseases. Conclusions Our study suggests complement components, such as CFHR1, CFHR2, C8G, C1QC, CFHR5, and C1S may be causally linked to non-viral liver diseases and could potentially serve as drug targets.