Mendelian Randomization Analysis of Hemostatic Factors and Their Contribution to Peripheral Artery Disease

Background: Peripheral artery disease (PAD) is the third most common form of atherosclerotic vascular disease and is characterized by significant functional disability and increased cardiovascular mortality. Recent genetic data support a role for a procoagulation protein variant, the factor V Leiden mutation, in PAD. The role of other hemostatic factors in PAD remains unknown. Objective: To evaluate the role of hemostatic factors in PAD using Mendelian randomization. Approach and Results: Two-sample Mendelian randomization to evaluate the roles of FVII (factor VII), FVIII (factor VIII), FXI (factor XI), VWF (von Willebrand factor), and fibrinogen in PAD was performed using summary statistics from GWAS for hemostatic factors performed within the Cohorts for Heart and Aging Research in the Genome Epidemiology Consortium and from GWAS performed for PAD within the Million Veteran Program. Genetically determined FVIII and VWF, but not FVII, FXI, or fibrinogen, were associated with PAD in Mendelian randomization experiments (FVIII: odds ratio, 1.41 [95% CI, 1.23–1.62], P =6.0×10 −7 , VWF: odds ratio, 1.28 [95% CI, 1.07–1.52], P =0.0073). In single variant sensitivity analysis, the ABO locus was the strongest genetic instrument for both FVIII and VWF. Conclusions: Our results suggest a role for hemostasis, and by extension, thrombosis in PAD. Further study is warranted to determine whether VWF and FVIII independently affect the biology of PAD.