Genetic variants in the immunoglobulin heavy chain locus are associated with the IgG index in multiple sclerosis

Abstract

Objective Intrathecal synthesis of immunoglobulin gamma (IgG) synthesis is frequently observed in patients with multiple sclerosis (MS). Whereas the extent of intrathecal IgG synthesis varies largely between patients, it remains rather constant in the individual patient over time. The aim of this study was to identify common genetic variants associated with the IgG index as a marker of intrathecal IgG synthesis in MS. Methods We performed a genome-wide association study of the IgG index in a discovery series of 229 patients. For confirmation we performed a replication in 2 independent series comprising 256 and 153 patients, respectively. The impact of associated single nucleotide polymorphisms (SNPs) on MS susceptibility was analyzed in an additional 1,854 cases and 5,175 controls. Results Significant association between the IgG index and 5 SNPs was detected in the discovery and confirmed in both replication series reaching combined p values of p = 6.5 × 10−11 to p = 7.5 × 10−16. All identified SNPs are clustered around the immunoglobulin heavy chain (IGHC) locus on chromosome 14q32.33 and are in linkage disequilibrium (r2 range, 0.71–0.95). The best associated SNP is located in an intronic region of the immunoglobulin gamma3 heavy chain gene. Additional sequencing identified the GM21* haplotype to be associated with a high IgG index. Further evaluation of the IGHC SNPs revealed no association with susceptibility to MS in our data set. Interpretation The extent of intrathecal IgG in MS is influenced by the IGHC locus. No association with susceptibility to MS was found. Therefore GM haplotypes might affect intrathecal IgG synthesis independently of the underlying disease

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

“…In this work, we investigate the association with MS of single nucleotide polymorphisms (SNPs) within the IGHC locus and their relationship with the intrathecal IgG and IgM synthesis, as well as with the presence of OCBs for both Igs. In addition to confirming the findings of Buck et al 14 regarding the association of the IGHC locus with the IgG index, we observed that the selected variant was associated with both MS susceptibility and IgM status.…”

“…SNP selection and genotyping SNP selection was based on the SNPs described by Buck et al 14 to the manufacturer's specifications. Genotyping call rates were >95% in each cohort analysed and 10% of the samples were genotyped in duplicate with >99% concordance.…”

“…In fact, about 95% of patients with MS show IgG-OCBs, and close to 40% show IgM OCBs in CSF. 8,9 Moreover, it has been reported that intrathecal IgM synthesis predicts a worse disease course in the first stages of MS. 10 Analysis of the IgG index, which is elevated in about 70% of patients, as well as the presence of OCBs 11,12 have been proposed as complementary data for the diagnosis of MS. 13 Buck et al 14 have recently reported that genetic variants in the immunoglobulin heavy chain (IGHC) locus are associated with the IgG index in MS, and that specific haplotypes might affect intrathecal IgG synthesis.…”

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.…”

G1m1 predominance of intrathecal virus‐specific antibodies in multiple sclerosis

“…It has been shown that genetic variants in the IGHG1 gene on chromosome 14 coding for the G1m allotypes on the IgG1 constant chain influence IgG levels in the CSF and MS risk 9, 10, 11. We recently demonstrated a dominance of plasmablasts carrying the G1m1 allotype in the CSF of G1m1/G1m3 heterozygous MS patients, as opposed to patients with neuroborreliosis 12.…”