A new risk variant for multiple sclerosis at the immunoglobulin heavy chain locus associates with intrathecal IgG, IgM index and oligoclonal bands

Abstract

Background:Recent findings have shown a correlation between the intrathecal IgG index and variants at the immunoglobulin heavy chain (IGHC) locus in patients with multiple sclerosis (MS). Objectives: The objective of this paper is to analyse the association of the locus with MS susceptibility and its relationship with intrathecal immunoglobulin (Ig) parameters. Methods: We genotyped the rs11621145 variant, located at the IGHC locus, in 2726 patients with MS and 2133 healthy controls. Associations of intrathecal IgG and IgM indexes with rs11621145 were analysed by linear regression analysis in 538 MS patients. Results: We found that rs11621145 showed statistically significant evidence for association with susceptibility to MS (odds ratio = 0.69, p = 1.053E-09), though validation of this result in additional cohorts would be desirable. We confirmed the association between the IgG index and the rs11621145 (p = 6.85E-07, Beta = 0.207). Furthermore, rs11621145 was inversely correlated with IgM index (p = 7.24E-04, Beta = -0.277), and therefore marks a decreased likelihood of presenting IgM oligoclonal bands (odds ratio = 0.38, p = 2.35E-06). Conclusions: Our results suggest that the polymorphism of the IGHC locus could be altering the switching of the Ig isotype in B cells and it may be interfering with T-dependent and T-independent antibody responses.

Genetics of Multiple Sclerosis: An Overview and New Directions

“…A study has identified a genome-wide association for the extent of intrathecal immunoglobulin G (IgG) in MS (Buck et al 2013). The associated variants were located in the immunoglobulin heavy chain (IGHC) locus on chromosome 14q32.33, which was also implicated by an independent study (Delgado-Garcia et al 2015). Furthermore, a third study identified two novel associations within the MHC region and IgG index (Goris et al 2015).…”

Anti-Mycobacterial Antibodies in Paired Cerebrospinal Fluid and Serum Samples from Japanese Patients with Multiple Sclerosis or Neuromyelitis Optica Spectrum Disorder

“…Increased immunoglobulin G (IgG) intrathecal synthesis in the CNS is considered a hallmark of clinically defined MS [3]. Both elevated IgG index and oligoclonal bands (OCBs) are detectable in more than 90% of patients with MS [3].…”

Selective intrathecal enrichment of G1m1‐positive B cells in multiple sclerosis

“…Genetic markers of the IgG heavy chain genes known to be determinants of Gm allotype polymorphisms have recently been shown to be associated with intrathecal levels of IgG,5, 6, 7 age at onset,6 and disease risk 7. The intrathecal humoral immune response in MS is dominated by the IgG1 subclass,8 and an early study showed an increased G1m1 to G1m3 ratio of IgG1 in the CSF of G1m1/G1m3 heterozygous MS patients 9.…”