Multiple sclerosis (MS) is a severe neurodegenerative disease of polygenic
etiology affecting the central nervous system. In addition to genetic factors,
epigenetic mechanisms, primarily DNA methylation, which regulate gene
expression, play an important role in MS development and progression. In this
study, we have performed the first whole-genome DNA methylation profiling of
peripheral blood mononuclear cells in relapsing-remitting MS (RRMS) and
primary-progressive MS (PPMS) patients and compared them to those of healthy
individuals in order to identify the differentially methylated CpG-sites (DMSs)
associated with these common clinical disease courses. In addition, we have
performed a pairwise comparison of DNA methylation profiles in RRMS and PPMS
patients. All three pairwise comparisons showed significant differences in
methylation profiles. Hierarchical clustering of the identified DMS methylation
levels and principal component analysis for data visualization demonstrated a
clearly defined aggregation of DNA samples of the compared groups into separate
clusters. Compared with the control, more DMSs were identified in PPMS patients
than in RRMS patients (67 and 30, respectively). More than half of DMSs are
located in genes, exceeding the expected number for random distribution of DMSs
between probes. RRMS patients mostly have hypomethylated DMSs, while in PPMS
patients DMSs are mostly hypermethylated. CpG-islands and CpG-shores contain
60% of DMSs, identified by pairwise comparison of RRMS and control groups, and
79% of those identified by pairwise comparison of PPMS and control groups.
Pairwise comparison of patients with two clinical MS courses revealed 51 DMSs,
82% of which are hypermethylated in PPMS. Overall, it was demonstrated that
there are more changes in the DNA methylation profiles in PPMS than in RRMS.
The data confirm the role of DNA methylation in MS development. We have shown,
for the first time, that DNA methylation as an epigenetic mechanism is involved
in the formation of two distinct clinical courses of MS: namely, RRMS and PPMS.
Multiple sclerosis (MS) is a serious, incurable neurological disease. In 2009, the ANZgene studies detected the suggestive association of located upstream of CD40 gene in chromosome 20q13 (p = 1.3×10−7). Identification of the causal variant(s) in the CD40 locus leads to a better understanding of the mechanism underlying the development of autoimmune pathologies. We determined the genotypes of rs6074022, rs1883832, rs1535045, and rs11086996 in patients with MS (n = 1684) and in the control group (n = 879). Two SNPs were significantly associated with MS: rs6074022 (additive model C allele OR = 1.27, 95% CI = [1.12–1.45], p = 3×10−4) and rs1883832 (additive model T allele OR = 1.20, 95% CI = [1.05–1.38], p = 7×10−3). In the meta-analysis of our results and the results of four previous studies, we obtain the association p-value of 2.34×10−12, which confirmed the association between MS and rs6074022 at a genome-wide significant level. Next, we demonstrated that the model including rs6074022 only sufficiently described the association. From our analysis, we can speculate that the association between rs1883832 and MS was induced by LD, whereas rs6074022 was a marker in stronger LD with the functional variant or was the functional variant itself. Our results indicated that the functional variants were located in the upstream region of the gene CD40 and were in higher LD with rs6074022 than LD with rs1883832.
Relapsing-remitting multiple sclerosis (RRMS) is the most prevalent course of multiple sclerosis. It is an autoimmune inflammatory disease of the central nervous system. To investigate the gender-specific involvement of microRNAs (miRNAs) in RRMS pathogenesis, we compared miRNA profiles in peripheral blood mononuclear cells separately in men and women (eight RRMS patients versus four healthy controls of each gender) using high-throughput sequencing. In contrast to women, six downregulated and 26 upregulated miRNAs (padj < 0.05) were identified in men with RRMS. Genes encoding upregulated miRNAs are co-localized in DLK1-DIO3 imprinted locus on human chromosome 14q32. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis was performed in independent groups of men (16 RRMS patients and 10 healthy controls) and women (20 RRMS patients and 10 healthy controls). Increased expression of miR-431, miR-127-3p, miR-379, miR-376c, miR-381, miR-410 and miR-656 was again demonstrated in male (padj < 0.05), but not in female RRMS patients. At the same time, the expression levels of these miRNAs were lower in healthy men than in healthy women, whereas in RRMS men they increased and reached or exceeded levels in RRMS women. In general, we demonstrated that expression levels of these miRNAs depend both on “health–disease” status and gender. Network-based enrichment analysis identified that receptor tyrosine kinases-activated pathways were enriched with products of genes targeted by miRNAs from DLK1-DIO3 locus. These results suggest the male-specific involvement of these miRNAs in RRMS pathogenesis via regulation of PI3K/Akt signaling.
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