Susceptibility to multiple sclerosis is associated with the proximal immunoglobulin heavy chain variable region.

Abstract

15 immunoglobulin heavy chain constant (CH) and variable region (VH) polymorphisms were selected to span the entire length of the heavy chain cluster. These polymorphisms were examined in 34 sib pairs concordant for multiple sclerosis (MS) and in 23 sporadic MS patients. Allele frequencies were calculated for the 2 MS patient groups and compared with those found in a control population from the same geographical location and of similar ethnic background. No significant association was found between MS and the 7 CH region polymorphisms examined. However, a significant correlation between the MS phenotype and a VH2 family polymorphism was observed in both MS patient populations (familial MS patients x2 = 8.16, P < 0.005; sporadic MS patients x2 = 8.90, P < 0.005). One allele of the VH2-5 gene segment was found to be overrepresented in both MS groups. VH2-5 has recently been physically mapped close to the CH region, between 180 and 360 kb away. These results indicate that a locus near or within the CH-proximal VH region is associated with increased susceptibility to MS. (J. Clin.

Genome‐wide association studies of multiple sclerosis

“…As the molecular biology of the immune system was unveiled, it was natural to ask whether these were also involved in MS pathogenesis. Candidate gene studies in cohorts of tens or hundreds of individuals at the loci encoding T‐cell receptor alpha12, 13 and beta14, 15 loci, the immunoglobulin heavy‐chain genes16, 17 and the gene for myelin basic protein,18, 19 among others, produced inconsistent findings 20, 21. As became obvious in retrospect, such studies are underpowered to detect risk alleles for common complex disease, suffer from population stratification and other artefacts and often assess genes that have broad relevance to the immune system but do not drive disease risk per se 22…”

The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

“…For example, several association and linkage studies using IGH markers have been conducted in multiple sclerosis, two of which are referenced in Table 2. Whereas the use of a single IGHV2 subgroup-specific probe and restriction-fragment length polymorphism analysis yielded significant associations in two studies, 71,72 the use of microsatellite markers in the IGH cluster has not produced consistent findings, [73][74][75] suggesting that both the use of small patient cohorts and unrepresentative panels of genetic markers are important factors to consider when interpreting conflicting results. The source of DNA used should also be considered as somatic mutations are known to occur in DNA isolated from B cells, as well as EBV-transformed B cell lines.…”

Antibody repertoire analysis in polygenic autoimmune diseases

“…The positive effects of B‐cell depletion therapies and the observation that IGHV2 gene polymorphisms have been associated with susceptibility to MS75, 76 indicate that B‐cells and antibodies play a significant role in MS. Many autoantigens have been proposed as pathogenic antibody targets in MS, including those derived from the following.…”