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G3 (Bethesda). 2016 Jul 7;6(7):2073-9. doi: 10.1534/g3.116.030841.

Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients.

Author information

1
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.
2
Division of Neurology, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
3
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
4
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.
5
Department of Cell Biology and Immunology, Instituto de Parasitología y Biomedicina López Neyra (IPBLN), CSIC, 18100 Granada, Spain.
6
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.
7
Unidad de Esclerosis Múltiple, Hospital Universitario Virgen Macarena, 41071 Sevilla, Spain.
8
Laboratory for Neuroimmunology, Neurosciences, University of Leuven, 1022, Belgium.
9
Laboratory for Neuroimmunology, Neurosciences, University of Leuven, 1022, Belgium Department of Neurology, University Hospitals Leuven, University of Leuven, Belgium.
10
Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), 48940 Spain Achucarro Basque Center for Neuroscience, 48170 Spain.
11
Neurogenomiks Group, Universidad del País Vasco (UPV/EHU), 48940 Spain Achucarro Basque Center for Neuroscience, 48170 Spain IKERBASQUE, Basque Foundation for Science, 48011 Spain.
12
Servicio de Neurología, Hospital Universitario Basurto-Osakidetza, 48940 Bilbao, Spain.
13
Department of Human Genetics, Ruhr University, 44801 Bochum, Germany.
14
Department of Neurology, Medical Faculty, Heinrich Heine University, 40225 Düsseldorf, Germany.
15
Department of Neurology, University of Rostock, 18059 Germany.
16
Department of Neurology, University of Würzburg, 97080 Würzburg, Germany.
17
Department of Neurology, University Hospital Bern and University of Bern, 3010 Bern, Switzerland.
18
Institute for Clinical Neuroimmunology, Ludwig Maximilian University, 80539 Munich, Germany.
19
Department of Neurology, University of Würzburg, 97080 Würzburg, Germany Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, WI 53226.
20
Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany.
21
Department of Clinical Chemistry, Ludwig Maximilian University, 80539 Munich, Germany Institute of Laboratory Medicine and Human Genetics, 78224 Singen, Germany.
22
Department of Neurology, University of Würzburg, 97080 Würzburg, Germany Department of Neurology, Sozialstiftung Bamberg Hospital, 96049 Germany.
23
Department of Neurology, Focus Program Translational Neuroscience, University Medical Center of the Johannes Gutenberg-University Mainz, 55122 Germany.
24
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.
25
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.
26
Department of Neurology, UGC Neurociencias Clínicas. IBIMA-Hospital Regional Universitario de Málaga, 29010 Spain.
27
Research Laboratory, UGC Neurociencias Clínicas. IBIMA-Hospital Regional Universitario de Málaga, 29010 Spain.
28
Immunology and Neurology Service, Multiple Sclerosis Unit, Ramón y Cajal University Hospital-IRYCIS, 28034 Madrid, Spain.
29
Department of Neurology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos-IdISSC, 28040 Madrid, Spain.
30
Department of Immunology, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos-IdISSC, Madrid, Spain.
31
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.
32
Department of Clinical Neurology, Medical University of Innsbruck, 6020 Austria.
33
Department of Neurology, Medical University of Graz, 8010 Austria.
34
Department of Neurology, Medical University of Vienna, 1090 Austria.
35
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada carles@can.ubc.ca.

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.

KEYWORDS:

association; genetics; linkage; multiple sclerosis; plasminogen

PMID:
27194806
PMCID:
PMC4938660
DOI:
10.1534/g3.116.030841
[Indexed for MEDLINE]
Free PMC Article

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