Scientists map 38 protein pathways that drive blood clots, opening drug targets
Researchers identified dozens of biological mechanisms linking lifestyle factors and heart disease to venous thromboembolism, a potentially fatal blood clot condition affecting hundreds of thousands annually. The findings pinpoint specific proteins that could become drug targets, potentially expanding treatment options beyond current anticoagulants and reducing the burden of a costly, common condition.
Originaltitel: Proteomic insights into modifiable risk of venous thromboembolism and cardiovascular comorbidities
<p>Background: Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown.</p><p>Objectives: We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities.</p><p>Methods: A 2-stage network Mendelian randomization analysis was conducted to explore the associations between 15 MFs, 1151 blood proteins, and VTE using data from a genome-wide meta-analysis including 81 190 cases of VTE. We used protein data from 35 559 individuals as the discovery analysis, and from 2 independent studies including 10 708 and 54 219 participants as the replication analyses. Based on the identified proteins, we assessed the druggability and examined the cardiovascular pleiotropy.</p><p>Results: The network Mendelian randomization 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. Lowdensity lipoprotein receptor-related protein 12 (LRP12: 34.3%-58.1%) and coagulation factor (F)XI (20.6%-39.6%) mediated most of the associations between 3 obesity indicators and VTE. Likewise, coagulation FXI mediated most of the smoking-VTE association (40%; 95% CI, 20%-60%) and insomnia-VTE association (27%; 95% CI, 5%49%). Many VTE-associated proteins were highly druggable for thrombotic conditions. 1, and low-density lipoprotein receptor-related protein 4) were associated with VTE and its cardiovascular comorbidities.</p><p>Conclusion: This study suggests that coagulation FXI, a druggable target, is an important mediator of the associations of obesity, smoking, and insomnia with VTE risk.</p>