Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF

Author:

Huffman Jennifer E.123ORCID,de Vries Paul S.4,Morrison Alanna C.5,Sabater-Lleal Maria6ORCID,Kacprowski Tim7ORCID,Auer Paul L.8,Brody Jennifer A.9,Chasman Daniel I.1011,Chen Ming-Huei12ORCID,Guo Xiuqing1314,Lin Li-An515,Marioni Riccardo E.161718,Müller-Nurasyid Martina192021,Yanek Lisa R.22,Pankratz Nathan23,Grove Megan L.5,de Maat Moniek P. M.24ORCID,Cushman Mary25,Wiggins Kerri L.9,Qi Lihong26,Sennblad Bengt627,Harris Sarah E.1617,Polasek Ozren28,Riess Helene2930,Rivadeneira Fernando431,Rose Lynda M.10,Goel Anuj32,Taylor Kent D.1314,Teumer Alexander33,Uitterlinden André G.431,Vaidya Dhananjay2234,Yao Jie13,Tang Weihong35,Levy Daniel3,Waldenberger Melanie212936ORCID,Becker Diane M.2237,Folsom Aaron R.35,Giulianini Franco10,Greinacher Andreas38,Hofman Albert4,Huang Chiang-Ching8,Kooperberg Charles39ORCID,Silveira Angela6,Starr John M.1640ORCID,Strauch Konstantin1941,Strawbridge Rona J.6ORCID,Wright Alan F.1,McKnight Barbara42,Franco Oscar H.4,Zakai Neil25,Mathias Rasika A.2243,Psaty Bruce M.9444546,Ridker Paul M.1011,Tofler Geoffrey H.47,Völker Uwe7,Watkins Hugh32,Fornage Myriam515,Hamsten Anders6,Deary Ian J.1648,Boerwinkle Eric549,Koenig Wolfgang3050,Rotter Jerome I.1314,Hayward Caroline1ORCID,Dehghan Abbas4,Reiner Alex P.3944,O’Donnell Christopher J.2,Smith Nicholas L.444651

Affiliation:

1. Medical Research Council Human Genetics Unit, Medical Research Council Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom;

2. The Framingham Heart Study, Cardiovascular Epidemiology and Human Genomics Branch, National Heart, Lung, and Blood Institute, Framingham, MA;

3. The Framingham Heart Study, Framingham, MA, and the Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD;

4. Department of Epidemiology, Erasmus Medical Center, Rotterdam, The Netherlands;

5. Human Genetics Center, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX;

6. Cardiovascular Genetics and Genomics Group, Atherosclerosis Research Unit, Department of Medicine Solna, Karolinska Institute, Stockholm, Sweden;

7. Department of Functional Genomics, Interfaculty Institute for Genetics and Functional Genomics, University Medicine and Ernst-Moritz-Arndt University Greifswald, Greifswald, Germany;

8. Joseph J. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI;

9. Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA;

10. Division of Preventive Medicine, Brigham and Women’s Hospital, Boston, MA;

11. Harvard Medical School, Boston, MA;

12. Department of Neurology, Boston University School of Medicine, Boston, MA;

13. The Institute for Translational Genomics and Population Sciences, Los Angeles Biomedical Research Institute, and

14. Department of Pediatrics, Harbor-University of California at Los Angeles (UCLA) Medical Center, Torrance, CA;

15. Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX;

16. Centre for Cognitive Ageing and Cognitive Epidemiology, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom;

17. Centre for Genomic and Experimental Medicine, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Edinburgh, United Kingdom;

18. Queensland Brain Institute, University of Queensland, Brisbane, QLD, Australia;

19. Institute of Genetic Epidemiology, Helmholtz Centre Munich-German Research Center for Environmental Health, Neuherberg, Germany;

20. Department of Medicine I, Ludwig-Maximilians-University Munich, Munich, Germany;

21. German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany;

22. GeneSTAR Research Program, Division of General Internal Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD;

23. Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN;

24. Department of Hematology, Erasmus MC, Rotterdam, The Netherlands;

25. Departments of Medicine and Pathology, University of Vermont, Colchester, VT;

26. University of California at Davis, Davis, CA;

27. Science for Life Laboratory, Karolinska Institute, Stockholm, Sweden;

28. Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia;

29. Institute of Epidemiology II, Helmholtz Centre Munich-German Research Center for Environmental Health, Neuherberg, Germany;

30. Department of Internal Medicine II-Cardiology, University of Ulm Medical School, Ulm, Germany;

31. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands;

32. Radcliffe Department of Medicine, Division of Cardiovascular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, United Kingdom;

33. Study of Health in Pomerania/ Clinical and Epidemiological Research Department, Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany;

34. Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD;

35. Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, MN;

36. Research Unit of Molecular Epidemiology, Helmholtz Centre Munich-German Research Center for Environmental Health, Neuherberg, Germany;

37. Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD;

38. Institute of Immunology and Transfusion Medicine, Department of Transfusion Medicine, University Medicine Greifswald, Greifswald, Germany;

39. Fred Hutchinson Cancer Research Center, Seattle, WA;

40. Alzheimer Scotland Dementia Research Centre, Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom;

41. Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-University, Munich, Germany;

42. Department of Biostatistics, University of Washington, Seattle, WA;

43. Division of Allergy and Clinical Immunology, Department of Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD;

44. Department of Epidemiology, and

45. Department of Health Services, University of Washington, Seattle, WA;

46. Group Health Research Institute, Group Health Cooperative, Seattle, WA;

47. Royal North Shore Hospital, University of Sydney, Sydney, NSW, Australia;

48. Department of Psychology, University of Edinburgh, Edinburgh, United Kingdom;

49. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX;

50. German Heart Centre Munich, Munich Technical University, Munich, Germany; and

51. Seattle Epidemiologic Research and Information Center, Veterans Affairs Office of Research and Development, Seattle, WA

Abstract

Key Points Twelve independent, novel, low-frequency (n = 2) and rare (n = 10) genetic variants were associated with fibrinogen, FVII, FVIII, or vWF. Nine were within previously associated genes, and 3 novel candidate genes (KCNT1, HID1, and KATNB1) were confined to cohorts of African ancestry.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference71 articles.

1. Hemostatic risk factors for atherothrombotic disease: an epidemiologic view.;Folsom;Thromb Haemost,2001

2. Factor VII coagulant activity, factor VII -670A/C and -402G/A polymorphisms, and risk of venous thromboembolism.;Folsom;J Thromb Haemost,2007

3. Which hemostatic markers add to the predictive value of conventional risk factors for coronary heart disease and ischemic stroke? The Caerphilly Study.;Smith;Circulation,2005

4. Plasma fibrinogen level and the risk of major cardiovascular diseases and nonvascular mortality: an individual participant meta-analysis.;Danesh;JAMA,2005

5. Role of clotting factor VIII in effect of von Willebrand factor on occurrence of deep-vein thrombosis.;Koster;Lancet,1995

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