Proteomic insights into modifiable risk of venous thromboembolism and cardiovascular comorbidities
Journal of Thrombosis and Haemostasis, 2023
Yuan S., Xu F., Zhang H., Chen J., Ruan X., Li Y., Burgess S., Åkesson A., Li X., Gill D., Larsson S.
| Disease area | Application area | Sample type | Products |
|---|---|---|---|
CVD | Pathophysiology | Plasma |  Olink Explore 3072/384 |
Abstract
Introduction
Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown. We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities.
Methods
A two-stage network Mendelian randomization (MR) analysis was conducted to explore the associations between 15 MFs and 1,151 blood proteins with VTE using data from a genome-wide meta-analysis including 81,190 VTE. We used protein data from 35,559 individuals as the discovery analysis and from two independent studies including 10,708 and 54,219 participants respectively as the replication analyses. Based on identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy.
Results
The network MR analyses identified 10 MF-VTE, 86 MF-protein, and 34 protein-VTE associations. These associations were overall consistent in the replication analyses. Thirty-eight pathways with directionally consistent direct and indirect effects in the MF-protein-VTE pathway were identified. Low-density lipoprotein receptor-related protein 12 (LRP12, 34.3%-58.1%) and coagulation factor XI (20.6%-39.6%) mediated most of the associations between three obesity indicators and VTE. Likewise, coagulation factor XI mediated most of the smoking-VTE association (40%; 95% confidence interval 20%-60%) and insomnia-VTE association (27%; 95% confidence interval 5%-49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. Five proteins (interleukin-6 receptor subunit alpha, LRP12, prothrombin, angiopoietin-1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities.
Conclusions
This study suggested that coagulation factor XI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.