Web of Science: 7 cites, Scopus: 8 cites, Google Scholar: cites,
Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients
Sadovnick, A. Dessa (University of British Columbia)
Traboulsee, Anthony L. (University of British Columbia)
Bernales, Cecily Q. (University of British Columbia)
Ross, Jay P. (University of British Columbia)
Forwell, Amanda L. (University of British Columbia)
Yee, Irene M. (University of British Columbia)
Guillot-Noel, Lena (Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, France)
Fontaine, Bertrand (Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, France)
Cournu-Rebeix, Isabelle (Inserm U 1127, CNRS UMR 7225, Sorbonne Universités, UPMC Univ Paris 06 UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, France)
Alcina, Antonio (Instituto de Parasitología y Biomedicina "López-Neyra")
Fedetz, Maria (Hospital Universitario Virgen Macarena (Sevilla, Andalusia))
Izquierdo, Guillermo (Hospital Universitario Virgen Macarena (Sevilla, Andalusia))
Matesanz, Fuencisla (Instituto de Parasitología y Biomedicina "López-Neyra")
Hilven, Kelly (University of Leuven)
Dubois, Bénédicte (University Hospitals Leuven)
Goris, An (University of Leuven)
Astobiza, Ianire (Achucarro Basque Center for Neuroscience)
Alloza, Iraide (IKERBASQUE, Basque Foundation for Science)
Antigüedad, Alfredo (Hospital de Basurto (Bilbao, Biscaia))
Vandenbroeck, Koen (IKERBASQUE, Basque Foundation for Science)
Akkad, Denis A. (Ruhr University)
Aktas, Orhan (Heinrich Heine University)
Blaschke, Paul (University of Rostock)
Buttmann, Mathias (University of Würzburg)
Chan, Andrew (University Hospital Bern and University of Bern)
Epplen, Joerg T. (Ruhr University)
Gerdes, Lisa-Ann (Institute for Clinical Neuroimmunology, Ludwig Maximilian University)
Kroner, Antje (Medical College of Wisconsin)
Kubisch, Christian (University Medical Center Hamburg-Eppendorf)
Kümpfel, Tania (Ludwig Maximilian University)
Lohse, Peter (Institute of Laboratory Medicine and Human Genetics)
Rieckmann, Peter (Sozialstiftung Bamberg Hospital)
Zettl, Uwe K. (University of Rostock)
Zipp, Frauke (University Medical Center of the Johannes Gutenberg-University Mainz)
Bertram, Lars (Imperial College London)
Lill, Christina M (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Fernandez, Oscar (Instituto de Investigación Biomédica de Málaga (IBIMA))
Urbaneja, Patricia (Instituto de Investigación Biomédica de Málaga (IBIMA))
Leyva, Laura (Instituto de Investigación Biomédica de Málaga (IBIMA))
Alvarez-Cermeño, Jose Carlos (Instituto Ramón y Cajal de Investigación Sanitaria (Madrid))
Arroyo, Rafael (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC))
Garagorri, Aroa M. (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC))
García-Martínez, Angel (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC))
Villar, Luisa M. (Hospital Universitario Ramón y Cajal (Madrid))
Urcelay, Elena (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC))
Malhotra, Sunny (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Montalban, Xavier (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Comabella, Manuel (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Berger, Thomas (Medical University of Innsbruck)
Fazekas, Franz (Medical University of Graz)
Reindl, Markus (Medical University of Innsbruck)
Schmied, Mascha C. (Medical University of Vienna)
Zimprich, Alexander (Medical University of Vienna)
Vilariño-Güell, Carles (University of British Columbia)
Universitat Autònoma de Barcelona

Data: 2016
Resum: Multiple sclerosis (MS) is a prevalent neurological disease of complex etiology. Here, we describe the characterization of a multi-incident MS family that nominated a rare missense variant (p. G420D) in plasminogen (PLG) as a putative genetic risk factor for MS. Genotyping of PLG p. G420D (rs139071351) in 2160 MS patients, and 886 controls from Canada, identified 10 additional probands, two sporadic patients and one control with the variant. Segregation in families harboring the rs139071351 variant, identified p. G420D in 26 out of 30 family members diagnosed with MS, 14 unaffected parents, and 12 out of 30 family members not diagnosed with disease. Despite considerably reduced penetrance, linkage analysis supports cosegregation of PLG p. G420D and disease. Genotyping of PLG p. G420D in 14446 patients, and 8797 controls from Canada, France, Spain, Germany, Belgium, and Austria failed to identify significant association with disease (P = 0. 117), despite an overall higher prevalence in patients (OR = 1. 32; 95% CI = 0. 93-1. 87). To assess whether additional rare variants have an effect on MS risk, we sequenced PLG in 293 probands, and genotyped all rare variants in cases and controls. This analysis identified nine rare missense variants, and although three of them were exclusively observed in MS patients, segregation does not support pathogenicity. PLG is a plausible biological candidate for MS owing to its involvement in immune system response, blood-brain barrier permeability, and myelin degradation. Moreover, components of its activation cascade have been shown to present increased activity or expression in MS patients compared to controls; further studies are needed to clarify whether PLG is involved in MS susceptibility.
Ajuts: Instituto de Salud Carlos III P12-00555
Instituto de Salud Carlos III PI13-01527
Instituto de Salud Carlos III PI13-01466
Instituto de Salud Carlos III PI13-0879
Nota: Altres ajuts: This research was undertaken thanks to funding from the Canada Research Chair [950-228408] and Canada Excellence Research Chair programs [214444], Canadian Institutes of Health Research [MOP-137051], Vancouver Coastal Health Research Institute, the Milan & Maureen Ilich Foundation [11-32095000], and the Vancouver Foundation [ADV14-1597]. Replication studies received funding from the program "Investissements d'avenir" ANR-10-IAIHU-06. Junta de Andalucía -FEDER [grant number CTS2704 to F.M.]. B.D. is a Clinical Investigator of the Research Foundation Flanders (FWO-Vlaanderen). A.G. and B.D. are supported by the Research Fund KU Leuven (OT/11/087 and CREA/14/023) and the Research Foundation Flanders (G073415N). A.L.T. reports personal fees from Biogen Idec, Chugai, Medimmune, Teva Innovation, and EMD Serono, and grants and personal fees from Genzyme Sanofi and Roche. All other authors report no disclosures.
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: Article ; recerca ; Versió publicada
Matèria: Multiple sclerosis ; Genetics ; Linkage ; Association ; Plasminogen
Publicat a: G3, enomes , ISSN 2160-1836

DOI: 10.1534/g3.116.030841
PMID: 27194806


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