DNA Methylation Signatures of Multiple Sclerosis Occur Independently of Known Genetic Risk and Are Primarily Attributed to B Cells and Monocytes

Abstract

Epigenetic mechanisms can regulate how DNA is expressed independently of sequence and are known to be associated with various diseases. Among those epigenetic mechanisms, DNA methylation (DNAm) is influenced by genotype and the environment, making it an important molecular interface for studying disease etiology and progression. In this study, we examined the whole blood DNA methylation profiles of a large group of people with (pw) multiple sclerosis (MS) compared to those of controls. We reveal that methylation differences in pwMS occur independently of known genetic risk loci and show that they more strongly differentiate disease (AUC = 0.85, 95% CI 0.82–0.89, p = 1.22 × 10−29) than known genetic risk loci (AUC = 0.72, 95% CI: 0.66–0.76, p = 9.07 × 10−17). We also show that methylation differences in MS occur predominantly in B cells and monocytes and indicate the involvement of cell-specific biological pathways. Overall, this study comprehensively characterizes the immune cell-specific epigenetic architecture of MS.

The effect of type 1 diabetes protection and susceptibility associated HLA class II genotypes on DNA methylation in immune cells

“…19,34 DRB1 alleles seem to have effects both on DRB1 expression and on other HLA loci, 31,[35][36][37][38] and DRB1 expression also seems to be regulated by DNA methylation. [39][40][41][42] In earlier studies, DNA methylation changes in HLA-DRB1 region have been associated with autoimmune diseases such as psoriasis, 41 MS disease, 40 systemic lupus erythematosus (SLE) 43 and narcolepsy with cataplexy 44 and, at least in MS disease, this association seems to be mediated by the DRB1*15:01 variant. 40,42 Although hypomethylation of the region seems to associate with DRB1 expression, 41,42 otherwise there has been fairly limited research about its functional effects.…”

“…[39][40][41][42] In earlier studies, DNA methylation changes in HLA-DRB1 region have been associated with autoimmune diseases such as psoriasis, 41 MS disease, 40 systemic lupus erythematosus (SLE) 43 and narcolepsy with cataplexy 44 and, at least in MS disease, this association seems to be mediated by the DRB1*15:01 variant. 40,42 Although hypomethylation of the region seems to associate with DRB1 expression, 41,42 otherwise there has been fairly limited research about its functional effects. When Miller et al discovered SLE associated methylation changes in HLA-DRB1 in CD8 + T cells, they examined how these cells responded to stimulation.…”

Functional significance of DNA methylation: epigenetic insights into Sjögren’s syndrome

“…There is evidence that IFN-signaling and viral infection-related pathways are highly upregulated in monocytes involved in the pathogenesis of SjS ( 136 ). Like B and T cells, the function and biology of monocytes are also influenced by DNA methylation, predominantly in autoimmune diseases ( 134 , 137 ). In circulating monocytes from individuals with SjS, DNA methylation alterations appear primarily as hypomethylation.…”