Identification of Antithrombin-Modulating Genes. Role of LARGE, a Gene Encoding a Bifunctional Glycosyltransferase, in the Secretion of Proteins?
Por:
de la Morena-Barrio, ME, Buil, A, Anton, AI, Martinez-Martinez, I, Minano, A, Gutierrez-Gallego, R, Navarro-Fernandez, J, Aguila, S, Souto, JC, Vicente, V, Soria, JM, Corral, J
Publicada:
21 may 2013
Resumen:
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 alpha 1-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 glycoproteins.
Filiaciones:
de la Morena-Barrio, ME:
Reg Campus Int Excellence Campus Mare Nostrum Uni, HU Morales Meseguer, Serv Hematol Oncologi Med, Ctr Reg Hemodonac, Murcia, Spain
Anton, AI:
Reg Campus Int Excellence Campus Mare Nostrum Uni, HU Morales Meseguer, Serv Hematol Oncologi Med, Ctr Reg Hemodonac, Murcia, Spain
Inst Invest St Pau IIB St, Unitat Genom Malalties Complexes, Barcelona, Spain
Martinez-Martinez, I:
Reg Campus Int Excellence Campus Mare Nostrum Uni, HU Morales Meseguer, Serv Hematol Oncologi Med, Ctr Reg Hemodonac, Murcia, Spain
Minano, A:
Reg Campus Int Excellence Campus Mare Nostrum Uni, HU Morales Meseguer, Serv Hematol Oncologi Med, Ctr Reg Hemodonac, Murcia, Spain
Gutierrez-Gallego, R:
PRBB, IMIM Parc Salut Mar, Neurosci Res Program, Bioanal Grp, Barcelona, Spain
Pompeu Fabra Univ, PRBB, Dept Expt & Hlth Sci, Barcelona, Spain
Navarro-Fernandez, J:
Reg Campus Int Excellence Campus Mare Nostrum Uni, HU Morales Meseguer, Serv Hematol Oncologi Med, Ctr Reg Hemodonac, Murcia, Spain
Aguila, S:
Reg Campus Int Excellence Campus Mare Nostrum Uni, HU Morales Meseguer, Serv Hematol Oncologi Med, Ctr Reg Hemodonac, Murcia, Spain
Souto, JC:
Inst Invest St Pau IIB St, Unitat Hemostasia & Trombosis, Barcelona, Spain
Vicente, V:
Reg Campus Int Excellence Campus Mare Nostrum Uni, HU Morales Meseguer, Serv Hematol Oncologi Med, Ctr Reg Hemodonac, Murcia, Spain
Soria, JM:
Inst Invest St Pau IIB St, Unitat Genom Malalties Complexes, Barcelona, Spain
Corral, J:
Reg Campus Int Excellence Campus Mare Nostrum Uni, HU Morales Meseguer, Serv Hematol Oncologi Med, Ctr Reg Hemodonac, Murcia, Spain
Gold, Green Published
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