Background: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system caused by genetic and environmental factors. DNA methylation, an epigenetic mechanism that controls genome activity, may provide a link between genetic and environmental risk factors.
Objective: We sought to identify DNA methylation changes in CD4+ T cells in patients with relapsing-remitting (RR-MS) and secondary-progressive (SP-MS) disease and healthy controls (HC).
Methods: We performed DNA methylation analysis in CD4+ T cells from RR-MS, SP-MS, and HC and associated identified changes with the nearby risk allele, smoking, age, and gene expression.
Results: We observed significant methylation differences in the VMP1/MIR21 locus, with RR-MS displaying higher methylation compared to SP-MS and HC. VMP1/MIR21 methylation did not correlate with a known MS risk variant in VMP1 or smoking but displayed a significant negative correlation with age and the levels of mature miR-21 in CD4+ T cells. Accordingly, RR-MS displayed lower levels of miR-21 compared to SP-MS, which might reflect differences in age between the groups, and healthy individuals and a significant enrichment of up-regulated miR-21 target genes.
Conclusion: Disease-related changes in epigenetic marking of MIR21 in RR-MS lead to differences in miR-21 expression with a consequence on miR-21 target genes.
Digital Object Identifier (DOI)
The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by grants from the Swedish Research Council, the Swedish Association for Persons with Neurological Disabilities, the Swedish Brain Foundation, Petrus and Augusta Hedlunds Foundation, the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, AstraZeneca (AstraZeneca-Science for Life Laboratory collaboration) and grant R01HL104135 from the National Institutes of Health/National Heart, Lung and Blood Institute (GOLDN). S.S.-B. was funded by a contract from Instituto de Salud Carlos III FEDER (IFI14/00007) and Daniel Bravo Andreu Private Foundation. L.K. was supported by fellowship from the Margaretha af Ugglas Foundation.
Full details of experimental procedures are provided in Supplementary Methods.
Ruhrmann, Sabrina; Ewing, Ewoud; Piket, Eliane; Kular, Lara; Cetrulo Lorenzi, Julio Cesar; Fernandes, Sunjay Jude; Morikawa, Hiromasa; Aeinehband, Shahin; Sayols-Baixeras, Sergi; Aslibekyan, Stella; Absher, Devin M.; Arnett, Donna K.; Tegner, Jesper; Gomez-Cabrero, David; Piehl, Fredrik; and Jagodic, Maja, "Hypermethylation of MIR21 in CD4+ T Cells from Patients with Relapsing-Remitting Multiple Sclerosis Associates with Lower miRNA-21 Levels and Concomitant Up-Regulation of Its Target Genes" (2018). Epidemiology Faculty Publications. 29.