title: Multiple sclerosis susceptibility loci do not alter clinical and MRI outcomes in clinically isolated syndrome.
abstract: It has not yet been established whether genetic predictors of multiple sclerosis (MS) susceptibility also influence disease severity and accumulation of disability. Our aim was to evaluate associations between 16 previously validated genetic susceptibility markers and MS phenotype. Patients with clinically isolated syndrome verified by positive magnetic resonance imaging (MRI) and cerebrospinal fluid findings (n=179) were treated with interferon-β. Disability and volumetric MRI parameters were evaluated regularly for 2 years. Sixteen single-nucleotide polymorphisms (SNPs) previously validated as predictors of MS susceptibility in our cohort and their combined weighted genetic risk score (wGRS) were tested for associations with clinical (conversion to MS, relapses and disability) and MRI disease outcomes (whole brain, grey matter and white matter volumes, corpus callosum cross-sectional area, brain parenchymal fraction, T2 and T1 lesion volumes) 2 years from disease onset using mixed-effect models. We have found no associations between the tested SNPs and the clinical or MRI outcomes. Neither the combined wGRS predicted MS activity and progression over 2-year follow-up period. Power analyses confirmed 90% power to identify clinically relevant changes in all outcome variables. We conclude that the most important MS susceptibility loci do not determine MS phenotype and disease outcomes.
authors.affiliation: Department of Neurology and Center of Clinical Neuroscience, Charles University in Prague, 1st Faculty of Medicine and General University Hospital in Prague, Prague, Czech Republic. tomas.kalincik@unimelb.edu.au
authors.forename: T
authors.initials: T
authors.lastname: Kalincik
authors.forename: C R G
authors.initials: CR
authors.lastname: Guttmann
authors.forename: J
authors.initials: J
authors.lastname: Krasensky
authors.forename: M
authors.initials: M
authors.lastname: Vaneckova
authors.forename: P
authors.initials: P
authors.lastname: Lelkova
authors.forename: M
authors.initials: M
authors.lastname: Tyblova
authors.forename: Z
authors.initials: Z
authors.lastname: Seidl
authors.forename: P L
authors.initials: PL
authors.lastname: De Jager
authors.forename: E
authors.initials: E
authors.lastname: Havrdova
authors.forename: D
authors.initials: D
authors.lastname: Horakova
mesh_terms: D000293:Adolescent; D000328:Adult; D015415:Biomarkers / Q000134:cerebrospinal fluid; D001921:Brain / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000175:diagnosis / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide
chemical_list: D015415:Biomarkers