Meta-Analysis

. 2019 Jan 29;139(5):620-635.

doi: 10.1161/CIRCULATIONAHA.118.034532.

Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

Maria Sabater-Lleal^{1

2}, Jennifer E Huffman^{3

4}, Paul S de Vries^{5

6}, Jonathan Marten⁷, Michael A Mastrangelo⁸, Ci Song^{3

4}, Nathan Pankratz⁹, Cavin K Ward-Caviness¹⁰, Lisa R Yanek¹¹, Stella Trompet^{12

13}, Graciela E Delgado¹⁴, Xiuqing Guo¹⁵, Traci M Bartz¹⁶, Angel Martinez-Perez², Marine Germain^{17

18}, Hugoline G de Haan¹⁹, Ayse B Ozel²⁰, Ozren Polasek²¹, Albert V Smith²², John D Eicher⁴, Alex P Reiner^{23

24}, Weihong Tang²⁵, Neil M Davies²⁶, David J Stott²⁷, Jerome I Rotter¹⁵, Geoffrey H Tofler²⁸, Eric Boerwinkle^{5

29}, Moniek P M de Maat³⁰, Marcus E Kleber^{14

31}, Paul Welsh³², Jennifer A Brody³³, Ming-Huei Chen^{3

4}, Dhananjay Vaidya¹¹, José Manuel Soria², Pierre Suchon^{34

35}, Astrid van Hylckama Vlieg¹⁹, Karl C Desch³⁶, Ivana Kolcic²¹, Peter K Joshi³⁷, Lenore J Launer³⁸, Tamara B Harris³⁸, Harry Campbell³⁷, Igor Rudan³⁷, Diane M Becker¹¹, Jun Z Li²⁰, Fernando Rivadeneira³⁹, André G Uitterlinden³⁹, Albert Hofman^{6

40}, Oscar H Franco^{6

41}, Mary Cushman⁴², Bruce M Psaty^{23

33

43

44}, Pierre-Emmanuel Morange^{34

35}, Barbara McKnight^{16

45}, Michael R Chong⁴⁶, Israel Fernandez-Cadenas⁴⁷, Jonathan Rosand⁴⁸, Arne Lindgren^{49

50}; INVENT Consortium; MEGASTROKE Consortium of the International Stroke Genetics Consortium (ISGC); Vilmundur Gudnason^{51

52}, James F Wilson^{7

37}, Caroline Hayward⁷, David Ginsburg²⁰, Myriam Fornage^{5

53}, Frits R Rosendaal^{19

54}, Juan Carlos Souto⁵⁵, Lewis C Becker¹¹, Nancy S Jenny⁵⁶, Winfried März^{14

57

58}, J Wouter Jukema^{13

54

59}, Abbas Dehghan^{6

60}, David-Alexandre Trégouët^{17

18}, Alanna C Morrison⁵, Andrew D Johnson^{3

4}, Christopher J O'Donnell^{3

4

61}, David P Strachan⁶², Charles J Lowenstein⁸, Nicholas L Smith^{23

44

63}

Affiliations

¹ Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (M.S.-L.).
² Unit of Genomics of Complex Diseases, Institut d'Investigació Biomèdica Sant Pau, IIB-Sant Pau, Barcelona, Spain (M.S.-L., A.M.-P., J.M.S.).
³ Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham, MA (J.E.H., C.S., J.D.E., M.-H.C., A.D.J., C.J.O.).
⁴ Framingham Heart Study, MA (J.E.H., C.S., J.D.E., M.-H.C., A.D.J., C.J.O.).
⁵ Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health (P.S.d.V., E.B., M.F., A.C.M.), University of Texas Health Science Center at Houston.
⁶ Department of Epidemiology (P.S.d.V., A.H., O.H.F., A.D.), Erasmus University Medical Center, Rotterdam, the Netherlands.
⁷ Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine (J.M., J.F.W., C.H.), University of Edinburgh, Scotland.
⁸ Aab Cardiovascular Research Institute, University of Rochester Medical Center, NY (M.A.M., C.J.L.).
⁹ Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis (N.P.).
¹⁰ Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC (C.K.W.-C.).
¹¹ GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (L.R.Y., D.V., D.M.B., L.C.B.).
¹² Department of Geriatrics and Gerontology (S.T.), Leiden University Medical Center, the Netherlands.
¹³ Department of Cardiology (S.T., J.W.J.), Leiden University Medical Center, the Netherlands.
¹⁴ Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (G.E.D., M.E.K., W.M.).
¹⁵ Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA (X.G., J.I.R.).
¹⁶ Department of Biostatistics (T.M.B., B.M.), University of Washington, Seattle.
¹⁷ Institut national de la santé et de la recherche médicale (INSERM), UMR_S 1166, Team Genomics and Pathophysiology of Cardiovascular Diseases, Sorbonne Universités, Université Pierre-et-Marie-Curie, Paris, France (M.G., D.-A.T.).
¹⁸ ICAN Institute for Cardiometabolism and Nutrition, Paris, France (M.G., D.-A.T.).
¹⁹ Department of Clinical Epidemiology (H.G.d.H., A.v.H.V., F.R.R.), Leiden University Medical Center, the Netherlands.
²⁰ Department of Human Genetics (A.B.O., J.Z.L., D.G.), University of Michigan, Ann Arbor.
²¹ Faculty of Medicine, University of Split, Croatia (O.P., I.K.).
²² School of Public Health, Department of Biostatistics (A.V.S.), University of Michigan, Ann Arbor.
²³ Department of Epidemiology, (A.P.R., B.M.P., N.L.S.), University of Washington, Seattle.
²⁴ Fred Hutchinson Cancer Research Center, Seattle, WA (A.P.R.).
²⁵ Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis (W.T.).
²⁶ Medical Research Council Integrative Epidemiology Unit and Bristol Medical School (N.M.D.), University of Bristol, UK.
²⁷ Academic Section of Geriatrics, Faculty of Medicine (J.D.S.), University of Glasgow, UK.
²⁸ Royal North Shore Hospital, University of Sydney, Australia (G.H.T.).
²⁹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX (E.B.).
³⁰ Department of Hematology (M.P.M.d.M.), Erasmus University Medical Center, Rotterdam, the Netherlands.
³¹ Institute of Nutrition, Friedrich-Schiller-University Jena, Mannheim, Germany (M.E.K.).
³² Institute of Cardiovascular and Medical Sciences (P.W.), University of Glasgow, UK.
³³ Department of Medicine (J.A.B., B.M.P.), University of Washington, Seattle.
³⁴ Laboratory of Haematology, La Timone Hospital, Marseille, France (P.S., P.-E.M.).
³⁵ Institut national de la santé et de la recherche médicale (INSERM), UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, Marseille, France (P.S., P.-E.M.).
³⁶ Department of Pediatrics and Communicable Disease (K.D.C.), University of Michigan, Ann Arbor.
³⁷ Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics (P.K.J., H.C., I.R., J.F.W.), University of Edinburgh, Scotland.
³⁸ Laboratory of Epidemiology and Population Sciences National Institute on Aging, Bethesda, MD (L.J.L., T.B.H.).
³⁹ Department of Internal Medicine (F.R., A.G.U.), Erasmus University Medical Center, Rotterdam, the Netherlands.
⁴⁰ Department of Epidemiology, Harvard H.T. Chan School of Public Health, Boston, MA (A.H.).
⁴¹ Institute of Social and Preventive Medicine, University of Bern, Switzerland (O.H.F.).
⁴² Larner College of Medicine, University of Vermont, Colchester (M.C.).
⁴³ Department of Health Services (B.M.P.), University of Washington, Seattle.
⁴⁴ Kaiser Permanente Washington Research Institute, Kaiser Permanente Washington, Seattle (B.M.P., N.L.S.).
⁴⁵ Cardiovascular Health Research Unit (B.M.), University of Washington, Seattle.
⁴⁶ McMaster University, Population Health Research Institute, Population Health Research Institute, Biochemistry and Biomedical Sciences, Hamilton, Canada (M.R.C.).
⁴⁷ Stroke Pharmacogenomics and genetics, Department of Neurology, Institut d'Investigació Biomedica Sant Pau, IIB-Sant Pau, Barcelona, Spain (I.F.-C.).
⁴⁸ Massachusetts General Hospital, Broad Institute, Harvard Medical School, Boston (J.R.).
⁴⁹ Department of Clinical Sciences Lund, Neurology, Lund University, Sweden (A.L.).
⁵⁰ Department of Neurology and Rehabilitation Medicine, Neurology, Skåne University Hospital, Lund, Sweden (A.L.).
⁵¹ Icelandic Heart Association, Kopavogur (V.G.).
⁵² Faculty of Medicine, University of Iceland, Reykjavik (V.G.).
⁵³ Brown Foundation Institute of Molecular Medicine (M.F.), University of Texas Health Science Center at Houston.
⁵⁴ Einthoven Laboratory of Experimental Vascular Medicine (F.R.R., J.W.J.), Leiden University Medical Center, the Netherlands.
⁵⁵ Unit of Hemostasis and Thrombosis, Hospital de la Sant Creu i Sant Pau, Barcelona, Spain (J.C.S.).
⁵⁶ Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Colchester (N.S.J.).
⁵⁷ SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany (W.M.).
⁵⁸ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Mannheim, Germany (W.M.).
⁵⁹ Interuniversity Cardiology Institute of the Netherlands, Utrecht (J.W.J.).
⁶⁰ Department of Epidemiology and Biostatistics, Imperial College London, UK (A.D.).
⁶¹ Cardiology Section Administration, Boston VA Healthcare System, West Roxbury, MA (C.J.O.).
⁶² Population Health Research Institute, St George's, University of London, UK (D.P.S.).
⁶³ Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, WA (N.L.S.).

PMID: 30586737
PMCID: PMC6438386
DOI: 10.1161/CIRCULATIONAHA.118.034532

Meta-Analysis

Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

Maria Sabater-Lleal et al. Circulation. 2019.

. 2019 Jan 29;139(5):620-635.

doi: 10.1161/CIRCULATIONAHA.118.034532.

Authors

Affiliations

¹ Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden (M.S.-L.).
² Unit of Genomics of Complex Diseases, Institut d'Investigació Biomèdica Sant Pau, IIB-Sant Pau, Barcelona, Spain (M.S.-L., A.M.-P., J.M.S.).
³ Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham, MA (J.E.H., C.S., J.D.E., M.-H.C., A.D.J., C.J.O.).
⁴ Framingham Heart Study, MA (J.E.H., C.S., J.D.E., M.-H.C., A.D.J., C.J.O.).
⁵ Human Genetics Center, Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health (P.S.d.V., E.B., M.F., A.C.M.), University of Texas Health Science Center at Houston.
⁶ Department of Epidemiology (P.S.d.V., A.H., O.H.F., A.D.), Erasmus University Medical Center, Rotterdam, the Netherlands.
⁷ Medical Research Council Human Genetics Unit, Institute of Genetics and Molecular Medicine (J.M., J.F.W., C.H.), University of Edinburgh, Scotland.
⁸ Aab Cardiovascular Research Institute, University of Rochester Medical Center, NY (M.A.M., C.J.L.).
⁹ Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis (N.P.).
¹⁰ Environmental Public Health Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC (C.K.W.-C.).
¹¹ GeneSTAR Research Program, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (L.R.Y., D.V., D.M.B., L.C.B.).
¹² Department of Geriatrics and Gerontology (S.T.), Leiden University Medical Center, the Netherlands.
¹³ Department of Cardiology (S.T., J.W.J.), Leiden University Medical Center, the Netherlands.
¹⁴ Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany (G.E.D., M.E.K., W.M.).
¹⁵ Institute for Translational Genomics and Population Sciences, Department of Pediatrics and Medicine, LABioMed at Harbor-UCLA Medical Center, Torrance, CA (X.G., J.I.R.).
¹⁶ Department of Biostatistics (T.M.B., B.M.), University of Washington, Seattle.
¹⁷ Institut national de la santé et de la recherche médicale (INSERM), UMR_S 1166, Team Genomics and Pathophysiology of Cardiovascular Diseases, Sorbonne Universités, Université Pierre-et-Marie-Curie, Paris, France (M.G., D.-A.T.).
¹⁸ ICAN Institute for Cardiometabolism and Nutrition, Paris, France (M.G., D.-A.T.).
¹⁹ Department of Clinical Epidemiology (H.G.d.H., A.v.H.V., F.R.R.), Leiden University Medical Center, the Netherlands.
²⁰ Department of Human Genetics (A.B.O., J.Z.L., D.G.), University of Michigan, Ann Arbor.
²¹ Faculty of Medicine, University of Split, Croatia (O.P., I.K.).
²² School of Public Health, Department of Biostatistics (A.V.S.), University of Michigan, Ann Arbor.
²³ Department of Epidemiology, (A.P.R., B.M.P., N.L.S.), University of Washington, Seattle.
²⁴ Fred Hutchinson Cancer Research Center, Seattle, WA (A.P.R.).
²⁵ Division of Epidemiology and Community Health, University of Minnesota School of Public Health, Minneapolis (W.T.).
²⁶ Medical Research Council Integrative Epidemiology Unit and Bristol Medical School (N.M.D.), University of Bristol, UK.
²⁷ Academic Section of Geriatrics, Faculty of Medicine (J.D.S.), University of Glasgow, UK.
²⁸ Royal North Shore Hospital, University of Sydney, Australia (G.H.T.).
²⁹ Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX (E.B.).
³⁰ Department of Hematology (M.P.M.d.M.), Erasmus University Medical Center, Rotterdam, the Netherlands.
³¹ Institute of Nutrition, Friedrich-Schiller-University Jena, Mannheim, Germany (M.E.K.).
³² Institute of Cardiovascular and Medical Sciences (P.W.), University of Glasgow, UK.
³³ Department of Medicine (J.A.B., B.M.P.), University of Washington, Seattle.
³⁴ Laboratory of Haematology, La Timone Hospital, Marseille, France (P.S., P.-E.M.).
³⁵ Institut national de la santé et de la recherche médicale (INSERM), UMR_S 1062, Nutrition Obesity and Risk of Thrombosis, Marseille, France (P.S., P.-E.M.).
³⁶ Department of Pediatrics and Communicable Disease (K.D.C.), University of Michigan, Ann Arbor.
³⁷ Centre for Global Health Research, Usher Institute for Population Health Sciences and Informatics (P.K.J., H.C., I.R., J.F.W.), University of Edinburgh, Scotland.
³⁸ Laboratory of Epidemiology and Population Sciences National Institute on Aging, Bethesda, MD (L.J.L., T.B.H.).
³⁹ Department of Internal Medicine (F.R., A.G.U.), Erasmus University Medical Center, Rotterdam, the Netherlands.
⁴⁰ Department of Epidemiology, Harvard H.T. Chan School of Public Health, Boston, MA (A.H.).
⁴¹ Institute of Social and Preventive Medicine, University of Bern, Switzerland (O.H.F.).
⁴² Larner College of Medicine, University of Vermont, Colchester (M.C.).
⁴³ Department of Health Services (B.M.P.), University of Washington, Seattle.
⁴⁴ Kaiser Permanente Washington Research Institute, Kaiser Permanente Washington, Seattle (B.M.P., N.L.S.).
⁴⁵ Cardiovascular Health Research Unit (B.M.), University of Washington, Seattle.
⁴⁶ McMaster University, Population Health Research Institute, Population Health Research Institute, Biochemistry and Biomedical Sciences, Hamilton, Canada (M.R.C.).
⁴⁷ Stroke Pharmacogenomics and genetics, Department of Neurology, Institut d'Investigació Biomedica Sant Pau, IIB-Sant Pau, Barcelona, Spain (I.F.-C.).
⁴⁸ Massachusetts General Hospital, Broad Institute, Harvard Medical School, Boston (J.R.).
⁴⁹ Department of Clinical Sciences Lund, Neurology, Lund University, Sweden (A.L.).
⁵⁰ Department of Neurology and Rehabilitation Medicine, Neurology, Skåne University Hospital, Lund, Sweden (A.L.).
⁵¹ Icelandic Heart Association, Kopavogur (V.G.).
⁵² Faculty of Medicine, University of Iceland, Reykjavik (V.G.).
⁵³ Brown Foundation Institute of Molecular Medicine (M.F.), University of Texas Health Science Center at Houston.
⁵⁴ Einthoven Laboratory of Experimental Vascular Medicine (F.R.R., J.W.J.), Leiden University Medical Center, the Netherlands.
⁵⁵ Unit of Hemostasis and Thrombosis, Hospital de la Sant Creu i Sant Pau, Barcelona, Spain (J.C.S.).
⁵⁶ Department of Pathology and Laboratory Medicine, University of Vermont College of Medicine, Colchester (N.S.J.).
⁵⁷ SYNLAB Academy, SYNLAB Holding Deutschland GmbH, Mannheim, Germany (W.M.).
⁵⁸ Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Mannheim, Germany (W.M.).
⁵⁹ Interuniversity Cardiology Institute of the Netherlands, Utrecht (J.W.J.).
⁶⁰ Department of Epidemiology and Biostatistics, Imperial College London, UK (A.D.).
⁶¹ Cardiology Section Administration, Boston VA Healthcare System, West Roxbury, MA (C.J.O.).
⁶² Population Health Research Institute, St George's, University of London, UK (D.P.S.).
⁶³ Seattle Epidemiologic Research and Information Center, Department of Veterans Affairs Office of Research and Development, WA (N.L.S.).

PMID: 30586737
PMCID: PMC6438386
DOI: 10.1161/CIRCULATIONAHA.118.034532

Abstract

Background: Factor VIII (FVIII) and its carrier protein von Willebrand factor (VWF) are associated with risk of arterial and venous thrombosis and with hemorrhagic disorders. We aimed to identify and functionally test novel genetic associations regulating plasma FVIII and VWF.

Methods: We meta-analyzed genome-wide association results from 46 354 individuals of European, African, East Asian, and Hispanic ancestry. All studies performed linear regression analysis using an additive genetic model and associated ≈35 million imputed variants with natural log-transformed phenotype levels. In vitro gene silencing in cultured endothelial cells was performed for candidate genes to provide additional evidence on association and function. Two-sample Mendelian randomization analyses were applied to test the causal role of FVIII and VWF plasma levels on the risk of arterial and venous thrombotic events.

Results: We identified 13 novel genome-wide significant ( P≤2.5×10^-8) associations, 7 with FVIII levels ( FCHO2/TMEM171/TNPO1, HLA, SOX17/RP1, LINC00583/NFIB, RAB5C-KAT2A, RPL3/TAB1/SYNGR1, and ARSA) and 11 with VWF levels ( PDHB/PXK/KCTD6, SLC39A8, FCHO2/TMEM171/TNPO1, HLA, GIMAP7/GIMAP4, OR13C5/NIPSNAP, DAB2IP, C2CD4B, RAB5C-KAT2A, TAB1/SYNGR1, and ARSA), beyond 10 previously reported associations with these phenotypes. Functional validation provided further evidence of association for all loci on VWF except ARSA and DAB2IP. Mendelian randomization suggested causal effects of plasma FVIII activity levels on venous thrombosis and coronary artery disease risk and plasma VWF levels on ischemic stroke risk.

Conclusions: The meta-analysis identified 13 novel genetic loci regulating FVIII and VWF plasma levels, 10 of which we validated functionally. We provide some evidence for a causal role of these proteins in thrombotic events.

Keywords: cardiovascular diseases; factor VIII; genetics; genome-wide association studies; risk factors; von Willebrand factor.

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Figures

**Figure 1.. Manhattan plot for the transethnic analyses factor VIII (FVIII) and von Willebrand factor (VWF).**
Representation of genome-wide results for FVIII (A) and VWF (B). Loci named by closest gene. Black indicates novel associations.

**Figure 2.. Silencing candidate genes changes basal release and stimulated release of von Willebrand factor (VWF).**
Human umbilical vein endothelial cells were transfected with short interfering RNA (siRNA) against selected genes for 4 days; the media was changed; and the cells were cultured for 30 minutes for basal release (A) or were stimulated with histamine 10 μmol/L for 30 minutes (B). VWF was then measured in the supernatant by an ELISA. n=4±SD. All results are relative to VWF release after transfection with a scrambled control siRNA, which is set as reference (100%). *P<0.05. **P<0.01. ***P<0.001.

**Figure 3.. Mendelian randomization results.**
Results show odds ratio (OR) (95% CI) per every higher SD change in FVIII (A) and von Willebrand factor (VWF; B). CAD indicates coronary artery disease; CVD, cardiovascular disease; FVIII, factor VIII; IVW, inverse-variance-weighted method; IVW.adjusted, IVW factor VIII adjusted for the effects of VWF; and VTE, venous thromboembolism.

See this image and copyright information in PMC

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Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

Affiliations

Genome-Wide Association Transethnic Meta-Analyses Identifies Novel Associations Regulating Coagulation Factor VIII and von Willebrand Factor Plasma Levels

Authors

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Abstract

Figures

References

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Grants and funding

LinkOut - more resources

Full Text Sources

Medical

Research Materials

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