Elevated complement C3 in patients with familial hypercholesterolemia

Background and Purpose

Familial hypercholesterolemia (FH) is characterized by lifelong exposure to elevated LDL-C and markedly increased risk of premature atherosclerotic cardiovascular disease (ASCVD). However, considerable heterogeneity in clinical presentation and event occurrence persists among FH patients, indicating that mechanisms beyond lipid burden may contribute to disease progression. Given the established role of complement activation in vascular inflammation, we aimed to identify complement-centered immune–inflammatory proteomic networks associated with FH and its clinical stages.

Methods

Plasma samples from 32 FH patients and 33 normolipidemic controls underwent secretome-enriched LC–MS/MS–based proteomic profiling. Label-free quantification was performed following log₂ transformation, and differentially expressed proteins were identified using statistical testing with multiple comparison correction. To investigate coordinated biological regulation beyond isolated protein changes, weighted gene co-expression network analysis (WGCNA) was applied to construct protein modules associated with FH status. Disease-related modules were further examined using protein–protein interaction mapping and functional pathway enrichment analysis.

Results

A total of 989 differentially expressed proteins were identified, with a predominance of upregulated proteins in FH plasma, indicating a global shift toward immune activation. Network analysis revealed significant enrichment of complement-related pathways. Within complement-enriched modules, C3 emerged as a central hub node based on intramodular connectivity and network topology. (Figure 1)

Importantly, C3 demonstrated a stepwise increase from normolipidemic controls to FH patients without ASCVD and further to FH patients with established ASCVD, paralleling clinical disease severity. Alternative pathway–associated complement proteins were coordinately upregulated. CFHR family proteins increased in parallel with C3, reinforcing the association between complement activation and clinical ASCVD status in FH. (Figure 2)

Conclusions

FH demonstrates coordinated immune–inflammatory proteomic networks centered on C3-driven complement activation. The progressive increase in C3 across clinical stages suggests that complement activation may reflect inflammatory disease burden beyond LDL-C elevation. These findings support further evaluation of C3-centered complement signaling as a potential biomarker axis for risk stratification in FH.Figure 1Figure 2