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Brain. 2015 Mar;138(Pt 3):632-43. doi: 10.1093/brain/awu405. Epub 2015 Jan 22.

Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.

Author information

  • 11 Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium an.goris@med.kuleuven.be.
  • 21 Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium.
  • 32 Department of Neurology, Oslo University Hospital Ullevål, Oslo, Norway 3 Institute of Clinical Medicine, University of Oslo, Norway.
  • 44 Department of Neurology, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.
  • 52 Department of Neurology, Oslo University Hospital Ullevål, Oslo, Norway.
  • 65 Norwegian MS-Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway.
  • 75 Norwegian MS-Registry and Biobank, Department of Neurology, Haukeland University Hospital, Bergen, Norway 6 KG Jebsen Centre for MS-research, Department of Clinical Medicine, University of Bergen, Bergen, Norway.
  • 87 Department of Health Sciences, University of Eastern Piedmont, Novara, Italy 8 Interdisciplinary Research Centre of Autoimmune Diseases IRCAD, University of Eastern Piedmont, Novara, Italy.
  • 97 Department of Health Sciences, University of Eastern Piedmont, Novara, Italy.
  • 108 Interdisciplinary Research Centre of Autoimmune Diseases IRCAD, University of Eastern Piedmont, Novara, Italy 9 Neurology Unit, Scientific Institute, Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy.
  • 1111 Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy 11 Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
  • 1211 Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
  • 1310 Department of Neuro-rehabilitation, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy 11 Laboratory of Genetics of Neurological Complex Disorders, Institute of Experimental Neurology (INSPE), Division of Neuroscience, San Raffaele Scientific Institute, Milan, Italy.
  • 1412 Neuroimmunology Unit, Department of Clinical Neuroscience, Centrum for Molecular Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 1513 Multiple Sclerosis Research, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden.
  • 1614 Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
  • 1715 Department of Neurology, Technische Universität München, Munich, Germany 16 Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 1815 Department of Neurology, Technische Universität München, Munich, Germany.
  • 1917 Institute of Neurosciences, Neurochemistry Unit, Université Catholique de Louvain-la-Neuve, Louvain-la-Neuve, Belgium.
  • 2018 Danish Multiple Sclerosis Centre, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
  • 2119 Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.
  • 2220 Hunter Medical Research Institute, University of Newcastle, Australia.
  • 2321 School of Medicine, Gold Coast Campus, Griffith University QLD 4222, Australia.
  • 2423 Menzies Research Institute, University of Tasmania, Hobart, Australia.
  • 2524 Institute of Immunology and Infectious Diseases, Murdoch University, Australia 25 Centre for Neuromuscular and Neurological Disorders, University of Western Australia, Australia.
  • 2627 Department of Clinical Neurosciences, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
  • 2728 Department of Molecular Biology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
  • 281 Laboratory for Neuroimmunology, Section of Experimental Neurology, Department of Neurosciences, KU Leuven - University of Leuven, Leuven, Belgium 4 Department of Neurology, University Hospitals Leuven, KU Leuven - University of Leuven, Leuven, Belgium.

Abstract

Immunological hallmarks of multiple sclerosis include the production of antibodies in the central nervous system, expressed as presence of oligoclonal bands and/or an increased immunoglobulin G index-the level of immunoglobulin G in the cerebrospinal fluid compared to serum. However, the underlying differences between oligoclonal band-positive and -negative patients with multiple sclerosis and reasons for variability in immunoglobulin G index are not known. To identify genetic factors influencing the variation in the antibody levels in the cerebrospinal fluid in multiple sclerosis, we have performed a genome-wide association screen in patients collected from nine countries for two traits, presence or absence of oligoclonal bands (n = 3026) and immunoglobulin G index levels (n = 938), followed by a replication in 3891 additional patients. We replicate previously suggested association signals for oligoclonal band status in the major histocompatibility complex region for the rs9271640*A-rs6457617*G haplotype, correlated with HLA-DRB1*1501, and rs34083746*G, correlated with HLA-DQA1*0301 (P comparing two haplotypes = 8.88 × 10(-16)). Furthermore, we identify a novel association signal of rs9807334, near the ELAC1/SMAD4 genes, for oligoclonal band status (P = 8.45 × 10(-7)). The previously reported association of the immunoglobulin heavy chain locus with immunoglobulin G index reaches strong evidence for association in this data set (P = 3.79 × 10(-37)). We identify two novel associations in the major histocompatibility complex region with immunoglobulin G index: the rs9271640*A-rs6457617*G haplotype (P = 1.59 × 10(-22)), shared with oligoclonal band status, and an additional independent effect of rs6457617*G (P = 3.68 × 10(-6)). Variants identified in this study account for up to 2-fold differences in the odds of being oligoclonal band positive and 7.75% of the variation in immunoglobulin G index. Both traits are associated with clinical features of disease such as female gender, age at onset and severity. This is the largest study population so far investigated for the genetic influence on antibody levels in the cerebrospinal fluid in multiple sclerosis, including 6950 patients. We confirm that genetic factors underlie these antibody levels and identify both the major histocompatibility complex and immunoglobulin heavy chain region as major determinants.

© The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

KEYWORDS:

CSF; genetics; immunoglobulin; multiple sclerosis; oligoclonal bands

PMID:
25616667
[PubMed - indexed for MEDLINE]
PMCID:
PMC4408440
Free PMC Article
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