Plasma protein and venous thromboembolism: prospective cohort and mendelian randomisation analyses

Summary We conducted cohort and Mendelian randomisation (MR) analyses to examine the associations of circulating proteins with risk of venous thromboembolism (VTE) to provide evidence basis for disease prevention and drug development. Cohort analysis was performed in 11 803 participants without baseline VTE. Cox regression was used to estimate the associations between 257 proteins and VTE risk. A machine‐learning model was constructed to compare the importance of identified proteins and traditional risk factors. Genetic association data on VTE were obtained from a genome‐wide meta‐analysis (26 066 cases and 624 053 controls) and FinnGen (14 454 cases and 294 700 controls). The cohort analysis, including 353 incident VTE cases diagnosed during a 6.6‐year follow‐up, identified 21 proteins associated with VTE risk after false discovery rate correction. The machine‐learning model indicated that body mass index and von Willebrand factor (vWF) made the same as well as most of the contributions to the overall model prediction. MR analysis found that genetically predicted levels of vWF, SERPINE1 (plasminogen activator inhibitor 1, known as PAI‐1), EPHB4 (ephrin type‐B receptor 4), TYRO3 (tyrosine‐protein kinase receptor TYRO3), TNFRSF11A (tumour necrosis factor receptor superfamily member 11A), and BOC (brother of CDO) were causally associated with VTE risk.