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Blood. 2019 Jan 14. pii: blood-2018-05-849240. doi: 10.1182/blood-2018-05-849240. [Epub ahead of print]

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, United States; paul.s.devries@uth.tmc.edu.
2
Cardiovascular Medicine Unit, Department of Medicine, Karolinska Institutet, Center for Molecular Medicine, Karolinska University Hospital, Stockholm, Sweden.
3
Population Sciences Branch, National Heart, Lung, and Blood Institute, Framingham, MA, United States.
4
MRC Human Genetics Unit, Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, United Kingdom.
5
The Framingham Heart Study, Framingham, MA, United States.
6
Department of Laboratory Medicine and Pathology, University of Minnesota School of Medicine, Minneapolis, MN, United States.
7
Department of Biostatistics, University of Washington, Seattle, WA, United States.
8
Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Netherlands.
9
Vth Department of Medicine, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
10
Unit of Genomics of Complex Diseases, Institut d'Investigacio Biomedica Sant Pau (IIB-Sant Pau), Barcelona, Spain.
11
National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, NC, United States.
12
Department of Medicine, University of Washington, Seattle, WA, United States.
13
Department of Hematology, Erasmus University Medical Center, Rotterdam, Netherlands.
14
Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom.
15
Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, Netherlands.
16
Division of Epidemiology & Community Health, University of Minnesota School of Public Health, Minneapolis, MN, United States.
17
Royal North Shore Hospital, University of Sydney, Sydney, Australia.
18
Department of Neurology, Boston University, Boston, MA, United States.
19
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, United States.
20
MRC Integrative Epidemiology Unit, Bristol Medical School, University of Bristol, Bristol, United Kingdom.
21
Department of Neurology, Massachusetts General Hospital (MGH), Harvard Medical School, Boston, MA, United States.
22
Department of Neurology, Erasmus University Medical Center, Rotterdam, Netherlands.
23
Department of Neurology, University of Maryland School of Medicine and Baltimore VAMC, Baltimore, MD, United States.
24
Departments of Medicine, Epidemiology, and Health Services, University of Washington, Seattle, WA, United States.
25
Department of Epidemiology, University of Washington, Seattle, WA, United States.
26
INSERM U1219 Bordeaux Population Health Research Center, University of Bordeaux, Bordeaux, France.
27
The Institute for Translational Genomics and Population Sciences, Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, CA, United States.
28
Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, United States.
29
Unitat d'Hemostasia i Trombosi, Hospital de la Sant Creu i Sant Pau, Barcelona, Spain.
30
MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.
31
Cardiology Section, VA Boston Healthcare System, West Roxbury, MA, United States.

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 nine genome-wide association studies of plasma FVII levels (seven FVII activity and two 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 seven studies that measured FVII activity, and a secondary analysis included all nine studies. We provided functional genomic validation for newly identified significant loci by silencing candidate genes in a human liver cell line (HuH7) using siRNA and then measuring F7 mRNA 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, and venous thromboembolism. We identified two novel (REEP3 and JAZF1-AS1) and six 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, while silencing JAZF1 downregulated FVII. Mendelian randomization analyses suggest that FVII activity has a positive causal effect on the risk of ischemic stroke. Variants at REEP3 and JAZF1 contribute to FVII activity by regulating F7 expression levels. FVII activity appears to contribute to the etiology of ischemic stroke in the general population.

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