Proteomic insights into modifiable risk of venous thromboembolism and cardiovascular comorbidities

• Background: Venous thromboembolism (VTE) has been associated with several modifiable factors (MFs) and cardiovascular comorbidities. However, the mechanisms are largely unknown.Objectives: We aimed to decipher proteomic pathways underlying the associations of VTE with MFs and cardiovascular comorbidities.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.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.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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Kardiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cardiac and Cardiovascular Systems (hsv//eng)

Nyckelord

modifiable

proteomics

venous thrombosis

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)