Plasma N-Glycan Signatures Are Associated With a First Event of Venous Thromboembolism

Abstract

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.

Keywords: blood coagulation factors; glycoproteins; glycosylation; risk factors; venous thromboembolism.

Figure 1.

Flowchart of study population selection. BMI indicates body mass index; LDL-C, low-density lipoprotein-cholesterol; QC, quality control; and VTE, venous thromboembolism.

Figure 2.

Associations between representative N-glycans/glycosylation traits and venous thromboembolism (VTE) risk. A, Higher relative abundance of certain N-glycans and glycosylation traits associated with increased VTE risk. B, Higher relative abundance of certain N-glycans and glycosylation traits associated with decreased VTE risk. A4E indicates total 2,6-linked sialylation on tetra-antennary glycans; CA1, monoantennary complex–type glycans; CA2, diantennary complex–type glycans; CA4, tetra-antennary glycans; CB, total bisection in complex type group; CF, fucosylation of complex–type glycans; CFa, total antenna fucosylation in complex type group; DVT, deep vein thrombosis; and PE, pulmonary embolism.

Figure 3.

Significant associations between venous thromboembolism (VTE) risk–decreasing N-glycans, as well as glycosylation traits, and VTE-associated coagulant factors and clot lysis time. CA1 indicates monoantennary complex–type glycans; CA2, diantennary complex–type glycans; CLtime, clot lysis time; fib, fibrinogen activity; FII:C, factor II activity; FIX:Ag, factor IX antigen; and FXI:C, factor XI activity.

Figure 4.

Significant associations between venous thromboembolism (VTE) risk, increasing N-glycans, as well as glycosylation traits, and VTE-associated coagulation factors and clot lysis time. CA4 indicates tetra-antennary glycans; CF, fucosylation of complex–type glycans; CLtime, clot lysis time; fib, fibrinogen activity; FII:C, factor II activity; FIX:Ag, factor IX antigen; FXI:C, factor XI activity; and VWF, von Willebrand Factor.