Causal insights into the role of metabolites in venous thromboembolism pathogenesis: a metabolome-wide Mendelian randomization study

Abstract

Background: Venous thromboembolism (VTE) is a significant global health burden, and metabolic alterations play a key role in its pathogenesis. However, previous studies have been constrained by several limitations, hindering clarification of the causal role of metabolites.

Objectives: To comprehensively evaluate the causal roles of metabolites in the pathogenesis of VTE and determine whether metabolites mediate the relationships between modifiable risk factors and VTE.

Methods: Genetic associations involving 690 plasmas and 211 urinary metabolites were analyzed as exposures, while the outcomes for VTE were derived from a large-scale meta-analysis of genome-wide association studies. Metabolome-wide Mendelian randomization and colocalization analyses were performed to assess the causal role of metabolites in VTE. Metabolic pathway analysis was performed using MetOrigin, and druggability assessments were conducted to prioritize potential therapeutic targets. Additionally, a 2-step Mendelian randomization framework was employed to elucidate the mediating effects of metabolites on the relationships between modifiable risk factors and VTE.

Results: After Bonferroni correction, 51 plasma metabolites and 18 urinary metabolites were significantly associated with VTE risk. Colocalization evidence supported causal relationships for 37 metabolites with VTE. Eleven metabolic pathways were identified for VTE-related metabolites, and 6 metabolites were prioritized as potential therapeutic targets. Twenty-four modifiable risk factors were associated with 28 VTE-related metabolites, 7 of which were linked to VTE risk. Mediation analyses further revealed significant mediating effect of 8 metabolites on how 6 modifiable factors influenced VTE.

Conclusion: This study identifies potential metabolite biomarkers associated with VTE risk and uncovered the metabolic mediators between modifiable risk factors and VTE, offering new insights for future prevention and treatment strategies.

Keywords: Mediation analysis; Mendelian randomization; Metabolome; Risk factor; Venous thromboembolism.