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

dc.rights.licenseopenen_US
dc.contributor.authorDE VRIES, P. S.
dc.contributor.authorSABATER-LLEAL, M.
dc.contributor.authorHUFFMAN, J. E.
dc.contributor.authorMARTEN, J.
dc.contributor.authorSONG, C.
dc.contributor.authorPANKRATZ, N.
dc.contributor.authorBARTZ, T. M.
dc.contributor.authorDE HAAN, H. G.
dc.contributor.authorDELGADO, G. E.
dc.contributor.authorEICHER, J. D.
dc.contributor.authorMARTINEZ-PEREZ, A.
dc.contributor.authorWARD-CAVINESS, C. K.
dc.contributor.authorBRODY, J. A.
dc.contributor.authorCHEN, M. H.
dc.contributor.authorDE MAAT, M. P. M.
dc.contributor.authorFRANBERG, M.
dc.contributor.authorGILL, D.
dc.contributor.authorKLEBER, M. E.
dc.contributor.authorRIVADENEIRA, F.
dc.contributor.authorSORIA, J. M.
dc.contributor.authorTANG, W.
dc.contributor.authorTOFLER, G. H.
dc.contributor.authorUITTERLINDEN, A. G.
dc.contributor.authorVAN HYLCKAMA VLIEG, A.
dc.contributor.authorSESHADRI, Sudha
dc.contributor.authorBOERWINKLE, E.
dc.contributor.authorDAVIES, N. M.
dc.contributor.authorGIESE, A. K.
dc.contributor.authorIKRAM, M. K.
dc.contributor.authorKITTNER, S. J.
dc.contributor.authorMCKNIGHT, B.
dc.contributor.authorPSATY, B. M.
dc.contributor.authorREINER, A. P.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorSARGURUPREMRAJ, Muralidharan
dc.contributor.authorTAYLOR, K. D.
dc.contributor.authorCONSORTIUM, Invent
dc.contributor.authorFORNAGE, M.
dc.contributor.authorHAMSTEN, A.
dc.contributor.authorMARZ, W.
dc.contributor.authorROSENDAAL, F. R.
dc.contributor.authorSOUTO, J. C.
dc.contributor.authorDEHGHAN, A.
dc.contributor.authorJOHNSON, A. D.
dc.contributor.authorMORRISON, A. C.
dc.contributor.authorO'DONNELL, C. J.
dc.contributor.authorSMITH, N. L.
dc.date.accessioned2020-06-17T13:18:42Z
dc.date.available2020-06-17T13:18:42Z
dc.date.issued2019-02-28
dc.identifier.issn1528-0020 (Electronic) 0006-4971 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/7979
dc.description.abstractEnFactor 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.
dc.language.isoENen_US
dc.subject.enVINTAGE
dc.title.enA genome-wide association study identifies new loci for factor VII and implicates factor VII in ischemic stroke etiology
dc.title.alternativeBlooden_US
dc.typeArticle de revueen_US
dc.identifier.doi10.1182/blood-2018-05-849240en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed30642921en_US
bordeaux.journalBlooden_US
bordeaux.page967-977en_US
bordeaux.volume133en_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - U1219en_US
bordeaux.issue9en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03209225
hal.version1
hal.date.transferred2021-04-28T01:50:35Z
hal.exporttrue
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