Plasma <i>N</i> -Glycan Signatures Are Associated With a First Event of Venous Thromboembolism

BACKGROUND: Coagulation factors play important roles in the pathophysiology of venous thromboembolism (VTE), and most of them are glycoproteins, that is, proteins containing glycans attached. Although the connection between glycosylation and coagulation factors seems obvious, the association between glycosylation and VTE risk remains unexplored. We aimed to elucidate the association between N -glycans in plasma and VTE risk in the MEGA study (Multiple Environmental and Genetic Assessment of Risk Factors for Venous Thrombosis), a case-control study aiming to identify risk factors for VTE. METHODS: The total plasma N -glycomes of 491 VTE cases with a first idiopathic VTE and 472 controls were analyzed using a robust mass spectrometry platform. In total, 91 N -glycans were measured. The association between each N -glycan and the risk of a first VTE was analyzed with logistic regression models, adjusted for potential confounders. In addition, we also examined the associations between VTE-associated N -glycans as well as glycosylation features and VTE-associated coagulation factors with linear regression models. RESULTS: In the analysis, 466 idiopathic VTE cases and 454 controls were included. We found that fucosylation of complex-type glycans and the presence of more antennae in glycan structures were associated with an increased risk of VTE. Conversely, monoantennary and diantennary complex–type glycans, as well as oligomannose-type glycans, were associated with a reduced risk of VTE. The associations between glycan features and VTE risk were partially supported by their relationships with procoagulant factors. CONCLUSIONS: We demonstrated the relevance of plasma N -glycan signatures in the risk of a first VTE. Plasma N -glycome holds a strong potential for VTE risk stratification.