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Blood. 2019 Feb 28;133(9):967-977. doi: 10.1182/blood-2018-05-849240. Epub 2019 Jan 14.

A genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology.

Author information

1
Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX.
2
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, The Netherlands.
3
Unit of Genomics of Complex Diseases, Institut d'Investigació Biomèdica Sant Pau (IIB-Sant Pau), Barcelona, Spain.
4
Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Stockholm, Sweden.
5
Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
6
Population Sciences Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Framingham, MA.
7
The Framingham Heart Study, Framingham, MA.
8
Center for Population Genomics, Veterans Affairs (VA) Boston Healthcare System, Jamaica Plain, MA.
9
Medical Research Council (MRC) Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
10
Department of Medical Sciences and.
11
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
12
Department of Laboratory Medicine and Pathology, School of Medicine, University of Minnesota, Minneapolis, MN.
13
Department of Biostatistics, University of Washington, Seattle, WA.
14
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, The Netherlands.
15
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
16
National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC.
17
Department of Medicine, University of Washington, Seattle, WA.
18
Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands.
19
Department of Epidemiology and Biostatistics and.
20
Department of Stroke Medicine, Imperial College London, London, United Kingdom.
21
Institute of Nutrition, Friedrich Schiller University Jena, Mannheim, Germany.
22
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
23
Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, MN.
24
Royal North Shore Hospital, University of Sydney, Sydney, Australia.
25
Department of Neurology, Boston University, Boston, MA.
26
Glenn Biggs Institute for Alzheimer's and Neurodegenerative Diseases, University of Texas Health Sciences Center, San Antonio, TX.
27
Human Genome Sequencing Center, College of Medicine, Baylor University, Houston, TX.
28
MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
29
Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
30
Department of Neurology, Erasmus University Medical Center, Rotterdam, The Netherlands.
31
Department of Neurology, School of Medicine, University of Maryland, Baltimore, MD.
32
Baltimore VA Medical Center, Baltimore, MD.
33
Department of Medicine.
34
Department of Epidemiology, and.
35
Department of Health Services, University of Washington, Seattle, WA.
36
Kaiser Permanente Washington Research Institute, Kaiser Permanente Washington, Seattle, WA.
37
Fred Hutchinson Cancer Research Center, Seattle, WA.
38
Department of Epidemiology, University of Washington, Seattle, WA.
39
INSERM U1219, Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France.
40
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA.
41
Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX.
42
Synlab Academy, Synlab Holding Deutschland GmbH, Mannheim, Germany.
43
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University Graz, Graz, Austria.
44
Einthoven Laboratory of Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands.
45
Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, The Netherlands.
46
Unitat d'Hemostasia i Trombosi, Hospital de la Sant Creu i Sant Pau, Barcelona, Spain.
47
MRC-Public Health England Centre for Environment and Health, School of Public Health and.
48
UK Dementia Research Institute, Imperial College London, London, United Kingdom.
49
Cardiology Section, VA Boston Healthcare System, West Roxbury, MA; and.
50
Seattle Epidemiologic Research and Information Center, Office of Research and Development, Department of Veteran Affairs, Seattle, WA.

Abstract

Factor VII (FVII) is an important component of the coagulation cascade. Few genetic loci regulating FVII activity and/or levels have been discovered to date. We conducted a meta-analysis of 9 genome-wide association studies of plasma FVII levels (7 FVII activity and 2 FVII antigen) among 27 495 participants of European and African ancestry. Each study performed ancestry-specific association analyses. Inverse variance weighted meta-analysis was performed within each ancestry group and then combined for a trans-ancestry meta-analysis. Our primary analysis included the 7 studies that measured FVII activity, and a secondary analysis included all 9 studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using small-interfering RNA and then measuring F7 messenger RNA and FVII protein expression. Lastly, we used meta-analysis results to perform Mendelian randomization analysis to estimate the causal effect of FVII activity on coronary artery disease, ischemic stroke (IS), and venous thromboembolism. We identified 2 novel (REEP3 and JAZF1-AS1) and 6 known loci associated with FVII activity, explaining 19.0% of the phenotypic variance. Adding FVII antigen data to the meta-analysis did not result in the discovery of further loci. Silencing REEP3 in HuH7 cells upregulated FVII, whereas silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of IS. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of IS in the general population.

PMID:
30642921
PMCID:
PMC6396174
[Available on 2020-02-28]
DOI:
10.1182/blood-2018-05-849240

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