title: Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients.
abstract: 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.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: A Dessa
authors.initials: AD
authors.lastname: Sadovnick
authors.affiliation: Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Traboulsee
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Cecily Q
authors.initials: CQ
authors.lastname: Bernales
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Jay P
authors.initials: JP
authors.lastname: Ross
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Forwell
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
authors.forename: Irene M
authors.initials: IM
authors.lastname: Yee
authors.affiliation: 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.
authors.forename: Lena
authors.initials: L
authors.lastname: Guillot-Noel
authors.affiliation: 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.
authors.forename: Bertrand
authors.initials: B
authors.lastname: Fontaine
authors.affiliation: 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.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Cournu-Rebeix
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, 18100 Granada, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Alcina
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, 18100 Granada, Spain Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, 41071 Sevilla, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Fedetz
authors.affiliation: Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, 41071 Sevilla, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Izquierdo
authors.affiliation: Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, 18100 Granada, Spain.
authors.forename: Fuencisla
authors.initials: F
authors.lastname: Matesanz
authors.affiliation: Laboratory for Neuroimmunology, Neurosciences, University of Leuven, 1022, Belgium.
authors.forename: Kelly
authors.initials: K
authors.lastname: Hilven
authors.affiliation: Laboratory for Neuroimmunology, Neurosciences, University of Leuven, 1022, Belgium Department of Neurology, University Hospitals Leuven, University of Leuven, Belgium.
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Dubois
authors.affiliation: Laboratory for Neuroimmunology, Neurosciences, University of Leuven, 1022, Belgium.
authors.forename: An
authors.initials: A
authors.lastname: Goris
authors.affiliation: Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), 48940 Spain Achucarro Basque Center for Neuroscience, 48170 Spain.
authors.forename: Ianire
authors.initials: I
authors.lastname: Astobiza
authors.affiliation: Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), 48940 Spain Achucarro Basque Center for Neuroscience, 48170 Spain IKERBASQUE, Basque Foundation for Science, 48011 Spain.
authors.forename: Iraide
authors.initials: I
authors.lastname: Alloza
authors.affiliation: Servicio de Neurología, Hospital Universitario Basurto-Osakidetza, 48940 Bilbao, Spain.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Antigüedad
authors.affiliation: Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), 48940 Spain Achucarro Basque Center for Neuroscience, 48170 Spain IKERBASQUE, Basque Foundation for Science, 48011 Spain.
authors.forename: Koen
authors.initials: K
authors.lastname: Vandenbroeck
authors.affiliation: Department of Human Genetics, Ruhr University, 44801 Bochum, Germany.
authors.forename: Denis A
authors.initials: DA
authors.lastname: Akkad
authors.affiliation: Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
authors.forename: Orhan
authors.initials: O
authors.lastname: Aktas
authors.affiliation: Department of Neurology, University of Rostock, 18059 Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Blaschke
authors.affiliation: Department of Neurology, University of Würzburg, 97080 Würzburg, Germany.
authors.forename: Mathias
authors.initials: M
authors.lastname: Buttmann
authors.affiliation: Department of Neurology, University Hospital Bern and University of Bern, 3010 Bern, Switzerland.
authors.forename: Andrew
authors.initials: A
authors.lastname: Chan
authors.affiliation: Department of Human Genetics, Ruhr University, 44801 Bochum, Germany.
authors.forename: Joerg T
authors.initials: JT
authors.lastname: Epplen
authors.affiliation: Institute for Clinical Neuroimmunology, Ludwig Maximilian University, 80539 Munich, Germany.
authors.forename: Lisa-Ann
authors.initials: LA
authors.lastname: Gerdes
authors.affiliation: Department of Neurology, University of Würzburg, 97080 Würzburg, Germany Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226.
authors.forename: Antje
authors.initials: A
authors.lastname: Kroner
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kubisch
authors.affiliation: Institute for Clinical Neuroimmunology, Ludwig Maximilian University, 80539 Munich, Germany.
authors.forename: Tania
authors.initials: T
authors.lastname: Kümpfel
authors.affiliation: Department of Clinical Chemistry, Ludwig Maximilian University, 80539 Munich, Germany Institute of Laboratory Medicine and Human Genetics, 78224 Singen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Lohse
authors.affiliation: Department of Neurology, University of Würzburg, 97080 Würzburg, Germany Department of Neurology, Sozialstiftung Bamberg Hospital, 96049 Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Rieckmann
authors.affiliation: Department of Neurology, University of Rostock, 18059 Germany.
authors.forename: Uwe K
authors.initials: UK
authors.lastname: Zettl
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg-University Mainz, 55122 Germany.
authors.forename: Frauke
authors.initials: F
authors.lastname: Zipp
authors.affiliation: Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, 23562, Germany School of Public Health, Medicine, Imperial College London, SW7 2AZ, UK.
authors.forename: Lars
authors.initials: L
authors.lastname: Bertram
authors.affiliation: Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg-University Mainz, 55122 Germany Lübeck Interdisciplinary Platform for Genome Analytics, Institutes of Neurogenetics & Integrative and Experimental Genomics, University of Lübeck, 23562, Germany Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Spain.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Lill
authors.affiliation: Department of Neurology, UGC Neurociencias Clínicas. IBIMA-Hospital Regional Universitario de Málaga, 29010 Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez
authors.affiliation: Department of Neurology, UGC Neurociencias Clínicas. IBIMA-Hospital Regional Universitario de Málaga, 29010 Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Urbaneja
authors.affiliation: Research Laboratory, UGC Neurociencias Clínicas. IBIMA-Hospital Regional Universitario de Málaga, 29010 Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Leyva
authors.affiliation: Immunology and Neurology Service, Multiple Sclerosis Unit, Ramón y Cajal University Hospital-IRYCIS, 28034 Madrid, Spain.
authors.forename: Jose Carlos
authors.initials: JC
authors.lastname: Alvarez-Cermeño
authors.affiliation: Department of Neurology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos-IdISSC, 28040 Madrid, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Arroyo
authors.affiliation: Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos-IdISSC, Madrid, Spain.
authors.forename: Aroa M
authors.initials: AM
authors.lastname: Garagorri
authors.affiliation: Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos-IdISSC, Madrid, Spain.
authors.forename: Angel
authors.initials: A
authors.lastname: García-Martínez
authors.affiliation: Immunology and Neurology Service, Multiple Sclerosis Unit, Ramón y Cajal University Hospital-IRYCIS, 28034 Madrid, Spain.
authors.forename: Luisa M
authors.initials: LM
authors.lastname: Villar
authors.affiliation: Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos-IdISSC, Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Urcelay
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Spain.
authors.forename: Sunny
authors.initials: S
authors.lastname: Malhotra
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Montalban
authors.affiliation: Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, 08035 Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Comabella
authors.affiliation: Department of Clinical Neurology, Medical University of Innsbruck, 6020 Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Berger
authors.affiliation: Department of Neurology, Medical University of Graz, 8010 Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Fazekas
authors.affiliation: Department of Clinical Neurology, Medical University of Innsbruck, 6020 Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Reindl
authors.affiliation: Department of Neurology, Medical University of Vienna, 1090 Austria.
authors.forename: Mascha C
authors.initials: MC
authors.lastname: Schmied
authors.affiliation: Department of Neurology, Medical University of Vienna, 1090 Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Zimprich
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada carles@can.ubc.ca.
authors.forename: Carles
authors.identifier: 0000-0002-5612-5940
authors.initials: C
authors.lastname: Vilariño-Güell
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D002896:Chromosomes, Human, Pair 6 / Q000737:chemistry* / Q000378:metabolism; D059472:Exome; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010958:Plasminogen / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid
chemical_list: D010958:Plasminogen
keywords: association; genetics; linkage; multiple sclerosis; plasminogen