Sadovnick, A DessaTraboulsee, Anthony LBernales, Cecily QRoss, Jay PForwell, Amanda LYee, Irene MGuillot-Noel, LenaFontaine, BertrandCournu-Rebeix, IsabelleAlcina, AntonioFedetz, MariaIzquierdo, GuillermoMatesanz, FuencislaHilven, KellyDubois, BenedicteGoris, AnAstobiza, IanireAlloza, IraideAntigüedad, AlfredoVandenbroeck, KoenAkkad, Denis AAktas, OrhanBlaschke, PaulButtmann, MathiasChan, AndrewEpplen, Joerg TGerdes, Lisa-AnnKroner, AntjeKubisch, ChristianKümpfel, TaniaLohse, PeterRieckmann, PeterZettl, Uwe KZipp, FraukeBertram, LarsLill, Christina MFernandez, OscarUrbaneja, PatriciaLeyva, LauraAlvarez-Cermeño, Jose CarlosArroyo, RafaelGaragorri, Aroa MGarcia-Martinez, AngelVillar, Luisa MUrcelay, ElenaMalhotra, SunnyMontalban, XavierComabella, ManuelBerger, ThomasFazekas, FranzReindl, MarkusSchmied, Mascha CZimprich, AlexanderVilariño-Güell, Carles2023-01-252023-01-252016-05-17Sadovnick AD, Traboulsee AL, Bernales CQ, Ross JP, Forwell AL, Yee IM, et al. Analysis of Plasminogen Genetic Variants in Multiple Sclerosis Patients. G3 (Bethesda). 2016 Jul 7;6(7):2073-9http://hdl.handle.net/10668/10099Multiple 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.enAttribution 4.0 Internationalhttps://creativecommons.org/licenses/by/4.0/AssociationGeneticsLinkageMultiple sclerosisPlasminogenAdultAgedAmino Acid SequenceCase-Control StudiesChromosomes, Human, Pair 6ExomeFemaleGene ExpressionGenotypeHumansMaleMiddle AgedMultiple SclerosisPedigreePlasminogenPolymorphism, Single NucleotideRisk FactorsSequence AlignmentSequence Homology, Amino Acidresearch article27194806open accessSistema inmunológicoPermeabilidadVirulenciaVaina de mielinaBarrera hematoencefálicaEsclerosis múltiple10.1534/g3.116.0308412160-1836PMC4938660https://doi.org/10.1534/g3.116.030841https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4938660/pdf