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Genetic risk factors are associated with cerebrospinal fluid measures in multiple sclerosis

A Goris1, I Pauwels1, MW Gustavsen2,3, B Van Son4, K Hilven1, SD Bos2,3, EG Celius2, P Berg-Hansen2, J Aarseth5, K-M Myhr5,6, S D’Alfonso7,8, N Barizzone7, MA Leone8,9, F Martinelli Boneschi10,11, M Sorosina11, G poster 8.5 Keygen lifetime license Liberatore10,11, I Kockum12, T Olsson12, J Hillert12, L Alfredsson13, SK Bedri12, B Hemmer14, D Buck14, A Berthele14, B Knier14, V Biberacher14, V van Pesch15, C Sindic15, AB Oturai16, HB Søndergaard16, F Sellebjerg16, PE Jensen16, M Comabella17, X Montalban17, J Pérez-Boza17, S Malhotra17, J Lechner-Scott18, S Broadley19, M Slee20, B Taylor21, A Kermode22, P-A Gourraud23, S Sawcer24, BK Andreassen25, B Dubois1,4, HF Harbo2,3, the International Multiple Sclerosis Genetics Consortium

1KU Leuven, Department of Neurosciences, Leuven, Belgium, 2Oslo University Hospital, Department of Neurology, Oslo, Norway, 3University of Oslo, Institute of Clinical Medicine, Oslo, Norway, 4University Hospitals Leuven, Department of Neurology, Leuven, Belgium, 5Haukeland University Hospital, Department of Neurology, Bergen, Norway, 6University of Bergen, Department of Clinical Medicine, Bergen, Norway, 7University of Eastern Piedmont, Department of Health Sciences, Novara, Italy, 8University of Eastern Piedmont, Interdisciplinary Research Center of Autoimmune Diseases (IRCAD), Novara, Italy, 9AOU “Maggiore della Carità”, Novara, Italy, 10San Raffaele Scientific Institute, Department of Neuro-rehabilitation, Milan, Italy, 11San Raffaele Scientific Institute, Division of Neuroscience, Milan, Italy, 12Karolinska Institutet, Department of Clinical Neuroscience, Stockholm, Sweden, 13Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden, 14Technische Universität München, Department of Neurology, Munich, Germany, 15Université Catholique de Louvain-la-Neuve, Neurochemistry poster 8.5 Keygen lifetime license Unit, Louvain-la-Neuve, Belgium, 16Copenhagen University Hospital, Department of Neurology, Copenhagen, Denmark, 17Hospital Universitari Vall d’Hebron, Institut de Receca Vall d’Hebron, Barcelona, Spain, 18University of Newcastle, Hunter Medical Research Institute, Newcastle, Australia, 19Griffith University, School of Medicine, Queensland, Australia, 20Flinders University of South Australia, School of Medicine, Adelaide, Australia, 21University of Tasmania, Hobart, Australia, 22University of Western Australia, Centre for Neuromuscular and Neurological Disorders, Crawley, Australia, 23University of California San Francisco, School of Medicine, San Francisco, CA, United States, 24University of Cambridge, Department of Clinical Neurosciences, Cambridge, United Kingdom, 25University of Oslo, Department of Molecular Biology, Oslo, Norway

Background: Immunological hallmarks of multiple sclerosis (MS) are production of antibodies expressed as oligoclonal bands (OCB) and/or an increased level of immunoglobulin G compared to serum (IgG index) in the cerebrospinal fluid (CSF) of MS patients. However, the underlying differences between OCB positive and negative MS patients and reasons for variability in IgG index are not known.

Objectives: Our aim was to identify genetic factors influencing the variation in the antibody production in the CSF poster 8.5 Keygen lifetime license in MS.

Methods: We performed a genome-wide association screen in MS patients collected from eight countries for two traits: presence or absence of OCBs (N=3,026) and IgG index levels (N=938). This screening phase was followed by a replication in 3,917 additional MS patients from eight countries.

Results: The Major Histocompatibility Complex (MHC) region is the main determinant of presence of OCBs, with up to two-fold differences in the odds of being OCB positive depending on genotype combinations. We furthermore identify a region near the ELAC1/SMAD4 genes associated with OCB status. The previously reported Immunoglobulin Heavy Chain (IGHC) region and newly identified signals in the MHC region together explain 10% of the variation in IgG index. Both traits (OCB and IgG index) are associated with clinical features of disease such as female gender, lower age at onset and increased severity.

Conclusions: This is the largest study so far investigating the genetic influence on antibody production in the CSF in MS, including 6,976 MS patients from nine countries. We confirm that genetic factors underlie antibody production in the CSF in MS and identify both the MHC and IGHC region as major determinants.