N-glycan branching on plasma proteins: a sweet fingerprint of coronary artery disease

Cardiovascular diseases (CVD) are the leading cause of death globally, with coronary artery disease (CAD) as the most prevalent single cause. While previous studies, including our own, have highlighted the role of immunoglobulin G (IgG) glycosylation in CAD, the present study is the first to investigate the total plasma protein N-glycome as a potential biomarker of CAD. In this cross-sectional study, we analyzed total plasma protein N-glycans from three independent study populations using hydrophilic interaction ultra-high performance liquid chromatography with fluorescence detection (HILIC-UHPLC-FLR). Meta-analysis revealed significant glycan alterations in individuals with coronary atherosclerosis compared with individuals without CAD. Specifically, highly branched, complex N-glycans (triantennary and sialylated glycans) were significantly increased in CAD+ cases (Effect = 0.193, SE = 0.0761, padj = 0.0358), whereas monogalactosylated (Effect = -0.2464, SE = 0.0768, padj = 0.00814) and core fucosylated glycans (Effect = -0.2025, SE = 0.0818, padj = 0.0358) were significantly decreased. These changes are consistent with an increased presence of acute-phase glycoproteins and systemic inflammation in CAD+ individuals. Our findings demonstrate that CAD-associated glycomic alterations are not confined to IgG but are present across the total plasma protein N-glycome, providing a broader molecular view of disease-associated glycosylation changes. Future studies should explore the integration of plasma glycan signatures with other inflammatory and metabolic markers to refine CAD risk stratification strategies.