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

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An Goris, Ine Pauwels, Marte W Gustavsen, Brechtje van Son, Kelly Hilven, Steffan D Bos, Elisabeth Gulowsen Celius, Pål Berg-Hansen, Jan Aarseth, Kjell-Morten Myhr, Sandra D'Alfonso, Nadia Barizzone, Maurizio A Leone, Filippo Martinelli Boneschi, Melissa Sorosina, Giuseppe Liberatore, Ingrid Kockum, Tomas Olsson, Jan Hillert, Lars Alfredsson & 27 others Sahl Khalid Bedri, Bernhard Hemmer, Dorothea Buck, Achim Berthele, Benjamin Knier, Viola Biberacher, Vincent van Pesch, Christian Sindic, Annette Bang Oturai, Helle Bach Søndergaard, Finn Sellebjerg, Poul Erik H Jensen, Manuel Comabella, Xavier Montalban, Jennifer Pérez-Boza, Sunny Malhotra, Jeannette Lechner-Scott, Simon Broadley, Mark Slee, Bruce Taylor, Allan G Kermode, Pierre-Antoine Gourraud, Stephen J Sawcer, Bettina Kullle Andreassen, Bénédicte Dubois, Hanne F Harbo, International Multiple Sclerosis Genetics Consortium

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.

Original languageEnglish
JournalBrain
Volume138
Issue number3
Pages (from-to)632-43
Number of pages12
ISSN0006-8950
DOIs
Publication statusPublished - Mar 2015

    Research areas

  • Adolescent, Adult, Aged, Child, Child, Preschool, Europe, Female, Genetic Association Studies, Genetic Variation, Humans, Immunoglobulin G, Major Histocompatibility Complex, Male, Middle Aged, Multiple Sclerosis, Oligoclonal Bands, Polymorphism, Single Nucleotide, Severity of Illness Index, Smad4 Protein, Tumor Suppressor Proteins, Young Adult

ID: 161441041