Abstract
DNA methylation is an epigenetic mark that is influenced by environmental factors and is associated with changes to gene expression and phenotypes. It may link environmental exposures to disease etiology or indicate important gene pathways involved in disease pathogenesis. We identified genomic regions that are differentially methylated in T cells of patients with relapsing remitting multiple sclerosis (MS) compared to healthy controls. DNA methylation was assessed at 450,000 genomic sites in CD4+ and CD8+ T cells purified from peripheral blood of 94 women with MS and 94 healthy women, and differentially methylated regions were identified using bumphunter. Differential DNA methylation was observed near four loci: MOG/ZFP57, HLA-DRB1, NINJ2/LOC100049716, and SLFN12. Increased methylation of the first exon of the SLFN12 gene was observed in both T cell subtypes and remained present after restricting analyses to samples from patients who had never been on treatment or had been off treatment for more than 2.5 years. Genes near the regions of differential methylation in T cells were assessed for differential expression in whole blood samples from a separate population of 1,329 women with MS and 97 healthy women. Gene expression of HLA-DRB1, NINJ2, and SLFN12 was observed to be decreased in whole blood in MS patients compared to controls. We conclude that T cells from MS patients display regions of differential DNA methylation compared to controls, and corresponding gene expression differences are observed in whole blood. Two of the genes that showed both methylation and expression differences, NINJ2 and SLFN12, have not previously been implicated in MS. SLFN12 is a particularly compelling target of further research, as this gene is known to be down-regulated during T cell activation and up-regulated by type I interferons (IFNs), which are used to treat MS.
Highlights
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with onset during early adulthood, leading to demyelination and axonal degeneration that often progresses to physical and cognitive disability
Because microarray probes used to assess DNA methylation may be sensitive to SNPs in the probe sequences, we evaluated whether methylation at individual CpGs within differentially methylated regions (DMRs) corresponded to differences in genotypes
Our findings show that CD4+ and CD8+ T cells isolated from MS patients have regions of markedly increased or decreased methylation compared to cells isolated from healthy controls
Summary
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, with onset during early adulthood, leading to demyelination and axonal degeneration that often progresses to physical and cognitive disability. The cause of MS is unknown, genetic and environmental factors, and interactions between them, are known to contribute to disease risk.[1,2,3] Variation in human leukocyte antigen (HLA) genes represent the strongest genetic susceptibility factor for MS, with the strongest signal in HLA-DRB1. Genomewide association studies (GWAS) and custom chip-based studies have identified 200 MS-associated non-HLA loci.[4,5,6] Each of these genetic associations exerts only a modest effect size, and no genetic variant by itself is sufficient to cause MS, making the genetic contribution to MS etiology highly complex. The local linkage disequilibrium (LD) structure of most MS-associated loci makes the identification of true causal variants difficult. When inferring the most likely affected genes, a strong overrepresentation of immunologically relevant genes is observed, in particular for genes known to regulate T cell mediated immunity.[4,6]
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