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Table 1 Baseline characteristics of studies about DNA methylation and MS

From: Deciphering the role of DNA methylation in multiple sclerosis: emerging issues

Author [references] Tissue Sample Type of study Results
Mastronardi [28] Cortical white matter of brain and thymus Normal controls (n = 4) MS patients (n = 12) Candidate-gene DNA methylation approach 30 % demethylation in PAD2 gene promoter only in the white matter of MS patients
Ramagopalan [31] RBMCs 50 pairs of monozygotic discordant twins with MS (68 % RRMS) Candidate-gene DNA methylation approach No significant association between MS and methylation level of MCH2TA promoter IV
Baranzini [33] CD4+ T lymphocytes 3 pairs of discordant MS twins (2 RRMS and 1 SPP) Genome-wide DNA methylation approach No evidence of epigenome differences
Handel [32] PBMCs Benign MS (n = 48) malignant MS (n = 20) Candidate-gene DNA methylation approach No significant association between DNA methylation across HLA-DRB1*1501, HLA-DRB5 and MS severity
Ligget [34] cfpDNA RRMS(r) (n = 30) RRMS(e) (n = 29) healthy controls (n = 30) Genome-wide DNA methylation approach Differences in DNA methylation: in 15 promoters between RRMS(r) patients and healthy controls, in 14 promoters between RRMS(c) patients and healthy controls and in 5 promoters between RRMS(r) patients and RRMS(c) patients. CDKN2B gene displayed the most differentially methylated pattern [71.0 % methylation in RRMS(r) and 22.6 % in controls]
Janson [35] CD4+ T lymphocytes 7 healthy controls (n = 7) 10 RRMS patients (n = 17) [under natalizumab (n = 10), without treatment (n = 2), under glatiramer acetate (n = 3), under IFN-1b (n = 2)] Candidate-gene DNA methylation approach DNA hypomethylation in FOXP3 and IL-17 genes, in MS patients under no natalizumab therapy compared to healthy controls
Calabrese [29] PBMCs Healthy controls (n = 30) MS patients (n = 32) [RRMS (n = 31), SPMS (n = 1)] Candidate-gene DNA methylation approach Upregulation and overexpression of PAD2 gene promoter due to hypomethylation. No correlation with MS disease duration, EDSS, MRI activity in the entire sample or after stratification by gender. Mild correlation between PAD2 concentration in peripheral blood and EDSS, revealed by 63 % of the patients. No significant results for PAD4
Kumagai [36] Peripheral blood leukocytes (293T cells) Normal subjects (n = 19) MS subjects (n = 69) [PPMS (n = 7), RRMS (n = 50), SPMS (n = 12)] Candidate-gene DNA methylation approach Increased level of methylation in promoter 2 of SHP-1 in MS patients compared to healthy controls. No association between methylation in SHP-1 promoter and MS type, years of disease and EDSS score
Calabrese [39] PBMCs Healthy controls (n = 40) MS patients (n = 40) Candidate-gene DNA methylation approach Downregulation of TET2 and DNMT1 gene expression in MS PBMCs induced by defective methylation
Graves [38] CD4+ T lymphocytes Healthy controls (n = 28) RRMS patients (n = 30) Genome-wide DNA methylation approach Differences in DNA methylation in 38 different genes (19 within MHC region, 55 at non-HLA genetic loci). Highest signal at 6p21.32 of HLA-DRB1. Strong association between DNA methylation of HLA-DRB1 and HLA-DRB1 haplotype
Huynh [43] Brain tissue Healthy controls (n = 19) MS patients (n = 28) Genome-wide DNA methylation approach 220 hypomethylated DMRs (containing 1235 CpGs) and 319 hypermethylated DMRs (containing 1292 CpGs) revealed, with oligodendrocyte-specific genes and genes regulating oligodendrocyte survival among them
Bos [44] Whole blood, CD4+ and CD8+ T lymphocytes Healthy controls (n = 14) RRMS patients (n = 14) all females Genome-wide DNA methylation approach Differences among CD4+, CD8+ and WB cells in their overall DNA methylation. No consistent DNA methylation differences between MS and controls. Difference in methylation level of Forty CpG-sites between MS patients and controls. The most significantly associated sites: a probe near TMEM48 transcription start site, another probe in the first exon of APC2 and several CpG-sites within DNHD1 gene. Increased hypermethylation in CD8+ cells in patients with disease duration over 7 years or lower, compared to those with duration above 8 years
Maltby [45] CD8+ T lymphocytes Healthy controls (n = 28) RRMS patients (n = 30) Genome-wide DNA methylation approach 79 methylated CpGs detected in genes outside MHC locus, not previously related to MS. No overlap of sites with methylation changes between CD4+ and CD8+ T cells (compared with previous results). Strong association between methylation changes in FTL, ERG and DCAF4 genes and MS
Neven [46] Whole blood Healthy controls (n = 137) RRMS patients (n = 51) Genome-wide DNA methylation approach (repetitive elements) Hypermethylated Alu, LINE-1 and SAT-α repetitive elements in MS patients compared to healthy controls. Higher disability associated with hypomethylation in LINE-1 and hypomethylation in Alu. No significant association between methylation and MS course, age of MS onset, multisystem disorders, presence or amount of CSF oligoclonal bands and spinal cord relapse
  1. MS multiple sclerosis, PPMS primary progressive multiple sclerosis, SPMS secondary progressive multiple sclerosis, RRMS relapsing-remitting multiple sclerosis, RRMS (r) relapsing-remitting multiple sclerosis in remission, RRMS (e) relapsing-remitting multiple sclerosis in exacerbation, MRI magnetic resonance imaging, EDSS expanded disability status scale, RBMCs peripheral blood mononuclear cells, PAD2 peptidylarginine deiminase 2, PAD4 peptidylarginine deiminase 4, cfpDNA cell-free plasma DNA, CSF cerebrospinal fluid, IFN interferon, MCH major histocompatibility complex, HLA human leukocyte antigen, CDKN2B cyclin dependent kinase inhibitor 2B, IL interleukin, FOXP3 forkhead box P3, SHP-1 protein-tyrosine phosphatase SHP-1, DNMT1 DNA methyltransferase1, TET2 ten-eleven translocation methylcytosine dioxygenase 2, DMR differentially methylated region, FTL ferritin light chain, ERG ETS-related gene, DCAF4, DDB1- and CUL4-associated factor 4, THEM48 transmembrane protein 48, APC2 adenomatous polyposis coli protein 2, DNHD1 dynein heavy chain domain 1, MHC2TA class II transactivator gene promoter IV