Dessa Sadovnick, A.; Alcina, Antonio; Fedetz, María; Matesanz, F.; Vilariño-Güell, Carles; Dessa Sadovnick, A. et. al.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.We
also thank Généthon, L’Association Française contre les Myopathies
(AFM), la Fondation pour l’Aide à la Recherche sur la Sclérose en
Plaques (ARSEP), and the Biological Resources Centre (BRC) of The
French Multiple Sclerosis Genetics Group (CRB-REFGENSEP). 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. Fondo de Investigación
Sanitaria (FIS)-Instituto de Salud Carlos III (ISCIII)-Fondos
Europeos de Desarrollo Regional (FEDER), Unión Europea [grant numbers
P12/00555, PI13/01527, PI13/01466 and PI13/0879 to F.M., A.A.
and G.I.] and 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.Peer reviewe
