Identify epigenetic biomarkers associated with disease susceptibility and treatment in multiple sclerosis patients from underrepresented minority populations.

African American and Hispanic-Latino patients frequently develop earlier onset of MS and a more severe disease course. Few biomarker studies focus on these populations.

Following informed consent, peripheral blood biospecimens (n=47) were obtained from patients with MS and controls under an IRB-approved protocol. Approximately 64% of donors identified as Black or African American and 30% as white, Hispanic-Latino. Genomic DNA (gDNA) was purified from whole blood. Infinium MethylationEPIC bead arrays were utilized to characterize gDNA methylation. Data were normalized and filtered with the minfi R package (Aryee et al., 2014). Probes were removed from analysis due to low detection value, sex differences, CpG sites with known SNP's, and probe cross-reactivity.  The RUVnormalize R package (Jacob et al., 2016) was used to estimate unknown covariates in the dataset, some of which corresponded to disease modifying treatments.

Global and gene specific differential methylation was observed in independent analyses based on disease state and treatment. Disease state analysis revealed 11 differentially methylated regions (DMR’s) with an FDR <1E-77. Hierarchical cluster analysis of 174 sites of DNA methylation within those DMR’s was sufficient to differentiate MS donors from controls. KEGG analysis revealed an association with regulatory pathways of neoplastic cell proliferation and metastasis (FDR<1E-7). Analysis of the effects of one specific treatment, dimethyl fumarate (DMF), was performed in the absence of treatment-related corrections. These data suggested an association between DMF and cytokine signaling pathways.

We demonstrate an association of epigenetic biomarkers of neoplasia with MS. This work also suggests that parallel analyses can be performed in the presence and absence of corrections for immune therapies. These results may be of specific relevance in the regulation of disease pathogenesis in underrepresented minority populations.