Aeron M Small1,2, Jennifer E Huffman3, Derek Klarin3,4,5, Maria Sabater-Lleal6,7, Julie A Lynch8,9,10, Themistocles L Assimes11,12, Yan V Sun13,14, Donald Miller15,16, Matthew S Freiberg17,18, Alanna C Morrison19, Daniel J Rader20, Peter W F Wilson13,21, Kelly Cho3, Philip S Tsao11,12, Kyong-Mi Chang1,20, Nicholas L Smith22,23,24, Christopher J O'Donnell3,25, Paul S de Vries26, Scott M Damrauer1,27. 1. Corporal Michael J. Crescenz VA Medical Center, PA (A.M.S., K.-M.C., S.M.D.). 2. Department of Medicine, Yale University School of Medicine, New Haven, CT (A.M.S.). 3. Massachusetts Veterans Epidemiology Research and Information Center (MAVERIC), Boston VA Healthcare System (J.E.H., D.K., K.C., C.J.O.). 4. Department of Surgery, Massachusetts General Hospital, Boston (D.K.). 5. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA (D.K.). 6. Genomics of Complex Diseases, Research Institute of Hospital Sant Pau, IIB Sant Pau, Barcelona, Spain (M.S.-L.). 7. Cardiovascular Medicine Unit, Department of Medicine, Center for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden (M.S.-L.). 8. Department of Veterans Affairs, Salt Lake City Health Care System, UT (J.A.L.). 9. University of Massachusetts College of Nursing & Health Sciences, Boston (J.A.L.). 10. Center for Healthcare Organization and Implementation Research, Edith Nourse Rogers Memorial VA Hospital, Bedford, MA (J.A.L.). 11. VA Palo Alto Health Care System, Palo Alto, CA (T.L.A., P.S.T.). 12. Department of Medicine, Stanford University School of Medicine, CA (T.L.A., P.S.T.). 13. Atlanta VA Health Care System, Decatur, GA (Y.V.S., P.W.F.W.). 14. Department of Epidemiology, Emory University Rollins School of Public Health and Department of Biomedical Informatics, Emory University School of Medicine, Atlanta, GA (Y.V.S.). 15. Center for Healthcare Organization and Implementation Research, Edith Nourse Rogers Memorial Veterans Hospital, Bedford, MA (D.M.). 16. Boston University School of Medicine, MA (D.M.). 17. VA Tennessee Valley Healthcare System, Nashville (M.S.F.). 18. Vanderbilt University Medical Center, Nashville, TN (M.S.F.). 19. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Sciences Center at Houston (A.C.M.). 20. Department of Medicine (D.J.R., K.-M.C.), Perelman School of Medicine, University of Pennsylvania, Philadelphia. 21. Emory Clinical Cardiovascular Research Institute, Atlanta, Georgia (P.W.F.W.). 22. Department of Epidemiology, University of Washington, Seattle (N.L.S.). 23. Kaiser Permanente Washington Research Institute, Kaiser Permanente Washington, Seattle (N.L.S.). 24. Department of Veteran Affairs, Office of Research and Development, Seattle Epidemiologic Research and Information Center, WA (N.L.S.). 25. Cardiovascular Medicine Division, Department of Medicine, Brigham and Women's Hospital (C.J.O.), Harvard Medical School, Boston. 26. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Sciences Center at Houston (P.S.d.V.). 27. Department of Surgery (S.M.D.), Perelman School of Medicine, University of Pennsylvania, Philadelphia.
Abstract
BACKGROUND AND OBJECTIVE: 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. We evaluated 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.
BACKGROUND AND OBJECTIVE: 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. We evaluated 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.
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