Identification of antithrombin-modulating genes. Role of LARGE, a gene encoding a bifunctional

de la Morena-Barrio, María Eugenia; Buil, Alfonso; Antón, Ana Isabel; Martínez-Martínez, Irene; Miñano, Antornia; Gutiérrez Gallego, Ricardo, 1968-; Navarro-Fernández, José; Águila, Sonia; Souto, Juan Carlos; Vicente, Vicente; Soria, José Manuel; Corral, Javier

Identification of antithrombin-modulating genes. Role of LARGE, a gene encoding a bifunctional

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dc.contributor.author de la Morena-Barrio, María Eugeniaca
dc.contributor.author Buil, Alfonsoca
dc.contributor.author Antón, Ana Isabelca
dc.contributor.author Martínez-Martínez, Ireneca
dc.contributor.author Miñano, Antorniaca
dc.contributor.author Gutiérrez Gallego, Ricardo, 1968-ca
dc.contributor.author Navarro-Fernández, Joséca
dc.contributor.author Águila, Soniaca
dc.contributor.author Souto, Juan Carlosca
dc.contributor.author Vicente, Vicenteca
dc.contributor.author Soria, José Manuelca
dc.contributor.author Corral, Javierca
dc.date.accessioned 2015-05-13T10:41:56Z
dc.date.available 2015-05-13T10:41:56Z
dc.date.issued 2013ca
dc.description.abstract The haemostatic relevance of antithrombin together with the low genetic variability of SERPINC1, and the high heritability of plasma levels encourage the search for modulating genes. We used a hypothesis-free approach to identify these genes, evaluating associations between plasma antithrombin and 307,984 polymorphisms in the GAIT study (352 individuals from 21 Spanish families). Despite no SNP reaching the genome wide significance threshold, we verified milder positive associations in 307 blood donors from a different cohort. This validation study suggested LARGE, a gene encoding a protein with xylosyltransferase and glucuronyltransferase activities that forms heparin-like linear polysaccharides, as a potential modulator of antithrombin based on the significant association of one SNPs, rs762057, with anti-FXa activity, particularly after adjustment for age, sex and SERPINC1 rs2227589 genotype, all factors influencing antithrombin levels (p = 0.02). Additional results sustained this association. LARGE silencing inHepG2 and HEK-EBNA cells did not affect SERPINC1 mRNA levels but significantly reduced the secretion of antithrombin with moderate intracellular retention. Milder effects were observed on α1-antitrypsin, prothrombin and transferrin. Our study suggests LARGE as the first known modifier of plasma antithrombin, and proposes a new role for LARGE in modulating extracellular secretion of certain glycoproteinsen
dc.description.sponsorship This study was supported partially by 04515/GERM/06 (Fundación Séneca de la Región de Murcia), SAF2009-08993 and SAF2008/01859 (Spanish Ministerio de Ciencia y Tecnología & Fondo Europeo de Desarrollo Regional de la Unión Europea FEDER), PI-08/0756, PI-11/0184 and RECAVA RD06/0014/0039 & RD06/0014/0016 (Spanish Instituto de Salud Carlos III & Fondo Europeo de Desarrollo Regional de la Unión Europea FEDER), and Centre National du Genotypage (Evry, France). MEMB is a holder of a predoctoral research grant from Spanish Instituto de Salud Carlos III (FI09/00190). IMM is a researcher from Fundació n para la Formación e Investigación Sanitarias. JNF is a postdoctoral researcher of the University of Murcia. JM Soria was supported by ‘‘Programa d’ Estabilització d’Investigadors de la Direcció d’Estrategia i Coordinació del Departament de Salut’’ (Generalitat de Catalunya).en
dc.format.mimetype application/pdfca
dc.identifier.citation de la Morena-Barrio ME, Buil A, Anton AI, Martinez-Martinez I, Minano A, Gutierrez-Gallego R et al. Identification of antithrombin-modulating genes. Role of LARGE, a gene encoding a bifunctional. PLoS ONE. 2013;8(5):e64998. DOI: 10.1371/journal.pone.0064998ca
dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0064998
dc.identifier.issn 1932-6203ca
dc.identifier.uri http://hdl.handle.net/10230/23570
dc.language.iso engca
dc.publisher Public Library of Science (PLoS)ca
dc.relation.ispartof PLoS ONE. 2013;8(5):e64998
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2009-08993
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/SAF2008-01859
dc.rights 2013 de la Morena-Barrio et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.en
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.subject.other Glicoproteïnesca
dc.subject.other Metabolismeca
dc.title Identification of antithrombin-modulating genes. Role of LARGE, a gene encoding a bifunctionalen
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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