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FGL1 as a modulator of plasma D-dimer levels: exome-wide marker analysis of plasma tPA, PAI-1 and D-dimer

dc.rights.licenseopenen_US
dc.contributor.authorTHIBORD, Florian
dc.contributor.authorSONG, Ci
dc.contributor.authorPATTEE, Jack
dc.contributor.authorRODRIGUEZ, Benjamin A. T.
dc.contributor.authorCHEN, Ming-Huei
dc.contributor.authorO'DONNELL, Christopher J.
dc.contributor.authorKLEBER, Marcus E.
dc.contributor.authorDELGADO, Graciela E.
dc.contributor.authorGUO, Xiuqing
dc.contributor.authorYAO, Jie
dc.contributor.authorTAYLOR, Kent D.
dc.contributor.authorOZEL, Ayse Bilge
dc.contributor.authorBRODY, Jennifer A.
dc.contributor.authorMCKNIGHT, Barbara
dc.contributor.authorGYORGY, Beata
dc.contributor.authorSIMONSICK, Eleanor
dc.contributor.authorLEONARD, Hampton L.
dc.contributor.authorCARRASQUILLA, German D.
dc.contributor.authorGUINDO-MARTINEZ, Marta
dc.contributor.authorSILVEIRA, Angela
dc.contributor.authorTEMPRANO-SAGRERA, Gerard
dc.contributor.authorYANEK, Lisa R.
dc.contributor.authorBECKER, Diane M.
dc.contributor.authorMATHIAS, Rasika A.
dc.contributor.authorBECKER, Lewis C.
dc.contributor.authorRAFFIELD, Laura M.
dc.contributor.authorKILPELAINEN, Tuomas O.
dc.contributor.authorGRARUP, Niels
dc.contributor.authorPEDERSEN, Oluf
dc.contributor.authorHANSEN, Torben
dc.contributor.authorLINNEBERG, Allan
dc.contributor.authorHAMSTEN, Anders
dc.contributor.authorWATKINS, Hugh
dc.contributor.authorSABATER-LLEAL, Maria
dc.contributor.authorNALLS, Mike A.
hal.structure.identifierBordeaux population health [BPH]
dc.contributor.authorTREGOUET, David-Alexandre
dc.contributor.authorMORANGE, Pierre-Emmanuel
dc.contributor.authorPSATY, Bruce M.
dc.contributor.authorTRACY, Russel P.
dc.contributor.authorSMITH, Nicholas L.
dc.contributor.authorDESCH, Karl C.
dc.contributor.authorCUSHMAN, Mary
dc.contributor.authorROTTER, Jerome I.
dc.contributor.authorDE VRIES, Paul S.
dc.contributor.authorPANKRATZ, Nathan D.
dc.contributor.authorFOLSOM, Aaron R.
dc.contributor.authorMORRISON, Alanna C.
dc.contributor.authorMARZ, Winfried
dc.contributor.authorTANG, Weihong
dc.contributor.authorJOHNSON, Andrew D.
dc.date.accessioned2021-06-30T10:05:00Z
dc.date.available2021-06-30T10:05:00Z
dc.date.issued2021-04-20
dc.identifier.issn1538-7836 (Electronic) 1538-7836 (Linking)en_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/94937
dc.description.abstractEnBACKGROUND: Use of targeted exome-arrays with common, rare variants and functionally enriched variation has led to discovery of new genes contributing to population variation in risk factors. Plasminogen activator-inhibitor 1 (PAI-1), tissue plasminogen activator (tPA), and the plasma product D-dimer are important components of the fibrinolytic system. There have been few large-scale genome-wide or exome-wide studies of PAI-1, tPA and D-dimer. OBJECTIVES: We sought to discover new genetic loci contributing to variation in these traits using an exome-array approach. METHODS: Cohort level analyses and fixed effects meta-analyses of PAI-1 (n = 15,603), tPA (n = 6,876) and D-dimer (n = 19,306) from 12 cohorts of European ancestry with diverse study design were conducted, including single-variant analyses and gene-based burden testing. RESULTS: Five variants located in NME7, FGL1 and the fibrinogen locus, all associated with D-dimer levels, achieved genome-wide significance (P < 5 × 10(-8) ). Replication was sought for these 5 variants, as well as 45 well-imputed variants with P < 1 × 10(-4) in the discovery using an independent cohort. Replication was observed for 3 out of the 5 significant associations, including a novel and uncommon (0.013 allele frequency) coding variant p.Trp256Leu in FGL1 (Fibrinogen-Like-1) with increased plasma D-dimer levels. Additionally, a candidate-gene approach revealed a suggestive association for a coding variant (rs143202684-C) in SERPINB2, and suggestive associations with consistent effect in the replication analysis include an intronic variant (rs11057830-A) in SCARB1 associated with increased D-dimer levels. CONCLUSION: This work provides new evidence for a role of FGL1 in hemostasis.
dc.language.isoENen_US
dc.subject.enComputational biology
dc.subject.enExome
dc.subject.enFibrinogen
dc.subject.enFibrinolysis
dc.subject.enGenetic association study
dc.title.enFGL1 as a modulator of plasma D-dimer levels: exome-wide marker analysis of plasma tPA, PAI-1 and D-dimer
dc.typeArticle de revueen_US
dc.identifier.doi10.1111/jth.15345en_US
dc.subject.halSciences du Vivant [q-bio]/Santé publique et épidémiologieen_US
dc.identifier.pubmed33876560en_US
bordeaux.journalJournal of Thrombosis and Haemostasisen_US
bordeaux.hal.laboratoriesBordeaux Population Health Research Center (BPH) - UMR 1219en_US
bordeaux.institutionUniversité de Bordeauxen_US
bordeaux.institutionINSERMen_US
bordeaux.teamVINTAGEen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
hal.identifierhal-03274625
hal.version1
hal.date.transferred2021-06-30T10:05:06Z
hal.exporttrue
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