The role of fibrinolysis in vascular diseases in UK biobank

Excerpt

Vascular diseases are significant contributors to deaths worldwide [1]. Common vascular diseases such as coronary artery disease (CAD), stroke, and venous thromboembolism (VTE) are heritable [1]. Genome-wide association studies (GWAS) have identified many common vascular diseases linked variants (https://​www.​ebi.​ac.​uk/​gwas/​home) [2]. However, there remains missing heritability for common vascular diseases. The fibrinolytic system has been implicated in both arterial and venous vascular diseases [3, 4]. Studies of genetically modified mice have shown the importance of intact fibrinolysis for the prevention of thrombosis [5, 6]. The molecular mechanisms that regulate fibrin formation and fibrinolysis are well-defined [3‐6]. The fibrinolytic system prevents blood clots from growing due to the degradation of fibrin clots by the enzyme plasmin [3‐6]. The formation of plasmin from plasminogen is carefully regulated to prevent pathological fibrinolysis and bleeding. Moreover, thrombolytic therapy is an important treatment for several vascular diseases [7]. Nevertheless, fibrinolytic genetic variants remain to be linked to VTE [8]. Moreover, plasminogen deficiency has not been linked to vascular diseases [9]. We have used the two published UK biobank portals (https://​azphewas.​com/​ and https://​app.​genebass.​org/​) [10, 11] to access whole exome sequencing (WES) data for 20 genes including receptors involved in the fibrinolytic system, both at the level of single variant data and in collapsing analysis of rare variants. We have also accessed GWAS data through (https://​www.​ebi.​ac.​uk/​gwas/​home) for these 20 genes involved in the fibrinolytic system [2]. The aim was to investigate whether any fibrinolytic gene is involved in common arterial and venous vascular diseases. …