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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.

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Acknowledgements

We thank all contributors who collected clinical data, Drs J Volna, I Kovarova, V Ticha, E Krasulova, M Vachova, S Machalicka, J Kotalova, Y Benesova, P Praksova, P Stourac, M Dufek, E Meluzinova, J Pikova, E Houzvickova, D Zimova, J Sucha, V Sladkova, J Mares, and Drs B Healy, B Keenan and N Patsopoulos for consultations of statistical methodology. The study was supported by the Czech Ministries of Education and Health (NT13237-4/2012, MSM 0021620849, PRVOUK-P26/LF1/4, RVO-VFN64165/2012) and Biogen Idec.

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Correspondence to T Kalincik.

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Tomas Kalincik received compensation for travel and honoraria from Novartis, Biogen Idec, Sanofi Aventis, Teva and Merck Serono, and research fellowship from Multiple Sclerosis Research Australia. Charles RG Guttmann received consulting fees from Tibotec Therapeutics/Johnson & Johnson and research support from Teva. Zdenek Seidl, Manuela Vaneckova and Jan Krasensky received financial support for research activities from Biogen Idec. Michaela Tyblova received compensation for travel and honoraria from Biogen Idec, Sanofi Aventis, Teva and Merck Serono. Philip L De Jager received consulting fees from Biogen Idec, honorarium and research support from Biogen Idec and support for research activities from Merck Serono. Eva Havrdova received speaker honoraria and consulting fees from Biogen Idec, Merck Serono, Novartis, Genzyme and Teva, as well as support for research activities from Biogen Idec and Merck Serono. Dana Horakova received speaker honoraria and consulting fees from Biogen Idec, Merck Serono, Teva and Novartis, as well as support for research activities from Biogen Idec.

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Kalincik, T., Guttmann, C., Krasensky, J. et al. Multiple sclerosis susceptibility loci do not alter clinical and MRI outcomes in clinically isolated syndrome. Genes Immun 14, 244–248 (2013). https://doi.org/10.1038/gene.2013.17

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