Oligoclonal Band Status in Scandinavian Multiple Sclerosis Patients Is Associated with Specific Genetic Risk Alleles

Abstract

The presence of oligoclonal bands (OCB) in cerebrospinal fluid (CSF) is a typical finding in multiple sclerosis (MS). We applied data from Norwegian, Swedish and Danish (i.e. Scandinavian) MS patients from a genome-wide association study (GWAS) to search for genetic differences in MS relating to OCB status. GWAS data was compared in 1367 OCB positive and 161 OCB negative Scandinavian MS patients, and nine of the most associated SNPs were genotyped for replication in 3403 Scandinavian MS patients. HLA-DRB1 genotypes were analyzed in a subset of the OCB positive (n = 2781) and OCB negative (n = 292) MS patients and compared to 890 healthy controls. Results from the genome-wide analyses showed that single nucleotide polymorphisms (SNPs) from the HLA complex and six other loci were associated to OCB status. In SNPs selected for replication, combined analyses showed genome-wide significant association for two SNPs in the HLA complex; rs3129871 (p = 5.7×10−15) and rs3817963 (p = 5.7×10−10) correlating with the HLA-DRB1*15 and the HLA-DRB1*04 alleles, respectively. We also found suggestive association to one SNP in the Calsyntenin-2 gene (p = 8.83×10−7). In HLA-DRB1 analyses HLA-DRB1*15∶01 was a stronger risk factor for OCB positive than OCB negative MS, whereas HLA-DRB1*04∶04 was associated with increased risk of OCB negative MS and reduced risk of OCB positive MS. Protective effects of HLA-DRB1*01∶01 and HLA-DRB1*07∶01 were detected in both groups. The groups were different with regard to age at onset (AAO), MS outcome measures and gender. This study confirms both shared and distinct genetic risk for MS subtypes in the Scandinavian population defined by OCB status and indicates different clinical characteristics between the groups. This suggests differences in disease mechanisms between OCB negative and OCB positive MS with implications for patient management, which need to be further studied.

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). In addition, one novel loci proximal to ELAC1 and SMAD4 (rs9807334) showed association to OCB status.…”

Systems biology approach to late‐onset Alzheimer's disease genome‐wide association study identifies novel candidate genes validated using brain expression data and Caenorhabditis elegans experiments

“…HLA-DRA major histocompatibility complex, class II, DR alpha (chromosome 6) is an HLA class II alpha chain paralogue. HLA associations have been previously reported in Alzheimer’s disease [1], Parkinson’s disease [23,24], and multiple sclerosis [25,26]. In a recent article, the HLA locus provided support to the notion of a link between frontotemporal dementia and the immune system.…”

Oligoclonal bands and age at onset correlate with genetic risk score in multiple sclerosis

“…11 Gender, disease course, age at symptom onset (AAO), Expanded Disability Status Scale (EDSS), 12 multiple sclerosis severity score (MSSS), 13 OCB in CSF and information about MS in the family was recorded. OCB positivity was determined either by isoelectric focusing or agarose gel electrophoresis, both in the Oslo 14 and UCSF cohorts. The IgG index was not available for all patients, so was therefore not included in the analysis.…”