Goris A, Pauwels I, Gustavsen MW, van Son B, Hilven K, Bos SD, Celius EG, Berg-Hansen P, Aarseth J, Myhr KM, D'Alfonso S, Barizzone N, Leone MA, Martinelli Boneschi F, Sorosina M, Liberatore G, Kockum I, Olsson T, Hillert J, Alfredsson L, Bedri SK, Hemmer B, Buck D, Berthele A, Knier B, Biberacher V, van Pesch V, Sindic C, Bang Oturai A, Søndergaard HB, Sellebjerg F, Jensen PE, Comabella M, Montalban X, Pérez-Boza J, Malhotra S, Lechner-Scott J, Broadley S, Slee M, Taylor B, Kermode AG, Gourraud PA; International Multiple Sclerosis Genetics Consortium, Sawcer SJ, Andreassen BK, Dubois B, Harbo HF. Genetic variants are major determinants of CSF antibody levels in multiple sclerosis.Brain. 2015 Jan 22. pii: awu405. [Epub ahead of print]
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.
There has been a question about whether B cells and oligoclonal bands are the key to progression,but what this study says that genetics plays a part in this,just as genetics plays a part in susceptibility to MS. Is this surprising as most genes found so far are immune genes and immune cells are associated with autoimmunity of dealing with infections
One of the regions associated with oligoclonal bands is the HLA-DRB1*1501 which is the major MS susceptibiltiy gene and there is another major histocompatibility complex gene DQA1*0301 another gene is closed to either SMAD4 gene encodes a protein involved in signal transduction of the transforming growth factor-beta, which is a immunomodulatory cytokine and ELAC1 encodes the short form of ribonuclease (RNase) Z and is predicted to have a role in RNA processing and also the Antibody genes were an important factor
Labels: MS Genes