NEW YORK (GenomeWeb) – An international team led by investigators in Sweden and the US has identified a multiple sclerosis (MS)-related dip in methylation at an immune locus previously implicated in the neurological condition that appears to contribute to this disease risk by altering regulation in this region.
"Our integrative approach provides insights into the molecular mechanisms of MS susceptibility and suggests putative therapeutic strategies targeting a methylation-mediated regulation of the major risk gene," corresponding authors Maja Jagodic, a clinical neuroscience researcher at the Karolinska Institute, and Andrew Feinberg, an epigenetics researcher at Johns Hopkins, and their colleagues wrote.
The researchers brought together blood-based methylation array, targeted bisulfite sequencing, genotyping, and/or gene expression profiles for 14,259 individuals with MS and more than 171,300 controls as part of a multistage meta-analysis. The findings, appearing online today in Nature Communications, revealed hypomethylation at an HLA haplotype called DRB1*15 that appears to mediate MS risk by shifting HLA-DRB1 expression.
In the process, the team also tracked down a variant called rs9267649 that appears to protect against MS risk by boosting methylation in the same HLA-DRB1 region and diminishing HLA-DRB1 expression.
"DNA methylation in the HLA-DRB1 gene mediates the effect of the strongest MS risk variant HLA-DRB1*15:01 and of a protective HLA variant (rs9267649) which has not been previously reported, on HLA-DRB1 expression and the risk of MS," the authors wrote.
Along with more than 100 risk loci falling outside of the HLA immune locus, prior genome-wide association studies have uncovered a strong association between MS and an HLA class II haplotype that includes DRB1*15:01, the researchers explained. Because many MS-related loci appear to fall in regulatory portions of the genome, they set out to dig into the epigenetic and expression features involved in the HLA haplotype.
The team began by assessing 23 MS cases and 13 unaffected controls, using Illumina Infinium HumanMethylation450 BeachChip arrays to profile methylation in blood monocytes, the white blood cell precursors of antigen-presenting cells that employ HLA class II molecules. The analysis led to two differentially methylated regions in the MS-affected group, both influencing HLA-DRB1. Known ties between MS risk and the HLA-DRB1*15:01 locus prompted a closer investigation of that haplotype.
In a series of analyses done on whole blood or peripheral blood mononuclear cells from hundreds of thousands of additional cases and controls from three more cohorts, the team used a combination of methylation, genotype, and/or RNA sequence-based gene expression profiles to hammer out the nature of this interaction by causal inference testing, expression quantitative trait locus profiling, and conditional analyses.
In particular, the researchers' results suggest that MS risk at the HLA locus is mediated by DNA methylation that alters HLA-DRB1 expression, enhancing its expression in individuals with the risky HLA-DRB1*15:01 haplotype and dialing HLA-DRB1 expression back in the presence of the protective rs9267649 variant.
"Given the robust genetic association of the HLA region with susceptibility to immune-mediated disease, our findings, together with other studies, suggest a role for DNA methylation in the pathogenesis of MS and autoimmune diseases in general," the authors concluded. "This in turn opens new avenues for development of therapeutic strategies aiming at controlling immune reactions by modulating HLA protein levels."