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

INVENT Consortium, MEGASTROKE Consortium of the International Stroke Genetics Consortium

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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 metaanalysis 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 metaanalysis. 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.

Original languageEnglish (US)
Pages (from-to)967-977
Number of pages11
JournalBlood
Volume133
Issue number9
DOIs
StatePublished - 2019

Bibliographical note

Funding Information:
This work was supported by American Heart Association grant #17POST33350042 (P.S.d.V.) and National Institutes of Health (NIH), National Heart, Lung, and Blood Institute grant R01HL134894 (N.L.S.). M.S.-L. was partially supported by a European Hematology Association (EHA)–International Society on Thrombosis and Haemostasis (ISTH) fellowship and by the Swedish Heart-Lung Foundation (20160290), and is a recipient of a Miguel Servet contract from the Spanish Ministry of Health (ISCIII CP17/00142). Infrastructure for the CHARGE Consortium was supported in part by National Heart, Lung, and Blood Institute grant R01HL105756. D.G. contributed to this work as part of a Wellcome Trust funded Clinical Research Training Fellowship. N.M.D. works at the Medical Research Council (MRC) and the University of Bristol supported the MRC Integrative Epidemiology Unit (MC_UU_12013/1, MC_UU_12013/9, MC_UU_00011/1). The Atherosclerosis Risk in Communities (ARIC) study was carried out as a collaborative study supported by National Heart, Lung, and Blood Institute contracts (HHSN268201100005C, HHSN268201100006C, HHSN268201100007C, HHSN268201100008C, HHSN268201100009C, HHSN268201100010C, HHSN268201100011C, and HHSN268201100012C), R01HL087641, R01HL59367, and R01HL086694; NIH, National Human Genome Research Institute contract U01HG004402; and NIH contract HHSN268200625226C. Infrastructure was partly supported by grant number UL1RR025005, a component of the NIH and NIH Roadmap for Medical Research. Funding support for “Building on GWAS for National Heart, Lung, and Blood Institute diseases: the US CHARGE Consortium” was provided by the NIH through the American Recovery and Reinvestment Act of 2009 (ARRA) (5RC2HL102419). Cardiovascular Health Study (CHS) research was supported by National Heart, Lung, and Blood Institute contracts HHSN268201200036C, HHSN268200800007C, HHSN268200960009C, HHSN268201800001C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086; and National Heart, Lung, and Blood Institute grants U01HL080295, R01HL085251, R01HL087652, R01HL105756, R01HL103612, R01HL120393, and R01HL130114 with additional contribution from the National Institute of Neurological Disorders and Stroke (NINDS). Additional support was provided through R01AG023629 from the NIH, National Institute on Aging. A full list of principal CHS investigators and institutions can be found at CHS-NHLBI.org. The provision of genotyping data was supported in part by the NIH, National Center for Advancing Translational Sciences, Clinical and Translational Science Institute grant UL1TR000124, and the National Institute of Diabetes and Digestive and Kidney Disease Diabetes Research Center (DRC) grant DK063491 to the Southern California Diabetes Endocrinology Research Center. The Coronary Artery Risk Development in Young Adults Study (CARDIA) was conducted and supported by the National Heart, Lung, and Blood Institute in collaboration with the University of Alabama at Birmingham (HHSN268201300025C and HSN268201300026C), Northwestern University (HHSN268201300027C), University of Minnesota (HHSN268201300028C), Kaiser Foundation Research Institute (HHSN268201300029C), and Johns Hopkins University School of Medicine (HHSN268200900041C). CARDIA was also partially supported by the Intramural Research Program of the National Institute on Aging and an intra-agency agreement between the National Institute on Aging and the National Heart, Lung, and Blood Institute (AG0005). Genotyping was funded as part of the National Heart, Lung, and Blood Institute Candidate-gene Association Resource (N01-HC-65226) and the National Human Genome Research Institute Gene Environment Association Studies (GENEVA; U01-HG004729, U01-HG04424, and U01-HG004446). The Framingham Heart Study was partially supported by the National Heart, Lung, and Blood Institute’s Framingham Heart Study (contract no. N01-HC-25195) and its contract with Affymetrix, Inc for genotyping services (contract no. N02-HL-6-4278). A portion of this research used the Linux Cluster for Genetic Analysis (LinGA-II) funded by the Robert Dawson Evans Endowment of the Department of Medicine at Boston University School of Medicine and Boston Medical Center. The analyses reflect intellectual input and resource development from the Framingham Heart Study investigators participating in the SNP Health Association Resource (SHARe) project. J.E.H., C.S., M.-H.C., A.D.J., and C.J.O. were supported by National Heart, Lung and Blood Intramural Research Funds.

Funding Information:
The Genetic Analysis for Idiopathic Thrombophilia 2 (GAIT2) project was supported partially by grants PI-11/0184, PI-14/0582, and Red Inves-tigación Cardiovascular RD12/0042/0032 from the Instituto Carlos III (Fondo de Investigación Sanitaria [FIS]), and 2014SGR-402 from the Consolidated Research Group of the Generalitat de Catalunya. The LUdwigshafen RIsk and Cardiovascular Health (LURIC) study was supported by the 7th Framework Program RiskyCAD (grant agreement number 305739) of the European Union. The work of W.M. and M.E.K. was supported as part of the Competence Cluster of Nutrition and Cardiovascular Health (nutriCARD), which was funded by the German Federal Ministry of Education and Research. The Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis (MEGA) study was supported by the Netherlands Heart Foundation (NHS 98.113), the Dutch Cancer Foundation (RUL 99/1992), and the Netherlands Organisation for Scientific Research (912–03–033| 2003), and was partially supported by the GenMed LABEX (ANR-10-LABX-0013). The Precocious Coronary Artery DISease (PROCARDIS) study project was funded with 10 million Euros through the 6th Framework Program of the European Union (LSH-2005-2.1.1-1). It started in April 2007 and funding lasted until September 2011. Although the funding ended, PROCARDIS is still actively doing research in the field of coronary artery disease genetics. The generation and management of GWAS genotype data for the Rotterdam Study (RS) was supported by the Netherlands Organisation of Scientific Research NWO Investments (no. 175.010.2005.011, 911-03-012). This study was funded by the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) project no. 050-060-810. The Rotterdam Study was funded by Erasmus Medical Center and Erasmus University, Rotterdam; Netherlands Organization for the Health Research and Development (ZonMw); the Research Institute for Diseases in the Elderly (RIDE); the Ministry of Education, Culture and Science; the Ministry for Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam.

Funding Information:
Conflict-of-interest disclosure: W.M. reports grants and personal fees from AMGEN, BASF, Sanofi, Siemens Diagnostics, Aegerion Pharmaceuticals, Astrazeneca, Danone Research, Numares, Pfizer, and Hoffmann LaRoche; personal fees from MSD and Alexion; grants from Abbott Diagnostics, all outside of the submitted work; and is employed by Synlab Holding Deutschland GmbH. B.M.P. serves on the Data Safety Monitoring Board of a clinical trial funded by Zoll LifeCor and on the Steering Committee of the Yale Open Data Access Project funded by Johnson & Johnson. N.M.D. reports a grant for research unrelated to this work from the Global Research Awards for Nicotine Dependence (GRAND), an independent grant-making body funded by Pfizer. The remaining authors declare no competing financial interests.

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