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

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.

Biomarkers in multiple sclerosis

“…Two regions, the MHC locus and the immunoglobulin heavy chain locus (IGHC), showed significant association to both IgG index and oligoclonal bands (136). This confirmed a number of earlier, small cohort studies suggesting association of MHC and IGHC loci in CSF IgG and OCBs (137)(138)(139)(140)(141)(142)(143)(144)(145).…”

Concerted variation of the 3′ regulatory region of Ig heavy chain and Gm haplotypes across human continental populations

“…Furthermore, the genomic region encompassing HS1.2 and IGHG3 overlaps entirely with a slightly larger region (90 kb, chr14:106150000–106240000) densely populated with a number of variable SNP sites associated to different phenotypes (Buck et al, ; Goris et al, ; Hawcutt et al, ; Sun et al, ). In particular, two of them were found to be associated with increased levels of Ig G in the cerebrospinal fluid as compared to serum, a hallmark of Multiple Sclerosis (Buck et al, ).…”

The immunogenetics of neurological disease

“…42,43 In an attempt to correlate DRB1*15:01 with disease progression or severity, this allele was associated with the existence of oligoclonal bands and increased immunoglobulin (Ig)G levels in the cerebrospinal fluid (CSF) of MS cases. 44,45 In contrast, there has been no consistent reporting of other MS predisposing DRB1 alleles with respect to disease progression or severity. 38,46 DRB1*15:01 is most often observed in European populations as a segment of an extended haplotype with DQA1*01:02 and DQB1*06:02, and therefore it has been considered challenging to discriminate the main casual allele or locus.…”