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.
Genetic studies of patients with autoimmune diseases have shown that one of the most important roles in the developing of these diseases is played by a cluster of genes of the major histocompatibility complex (MHC), as compared with other genome areas. Information on the specific contribution of MHC alleles, mostly MHC class II ones, to the genetic predisposition to autoimmune diseases is crucial for understanding their pathogenesis. This review dwells on the most relevant aspects of this problem: namely, the correlation between carriage of certain MHC II alleles and an increased (positively associated allele) or reduced (negatively associated allele) probability of developing the most common autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, autoimmune thyroiditis, etc. The most universal haplotypes, DR3-DQ2 and DR4-DQ8, are positively associated with many of these diseases, while the universal allele HLA-DRB1*0701 is protective.
Multiple sclerosis (MS) is an autoimmune neuro-inflammatory disease arising from complex interactions of genetic, epigenetic, and environmental factors. Variations in genes of some microRNAs—key post-transcriptional regulators of many genes—can influence microRNAs expression/function and contribute to MS via expression changes of protein-coding target mRNA genes. We performed an association study of polymorphous variants of MIR146A rs2910164, MIR196A2 rs11614913, MIR499A rs3746444 MIR223 rs1044165 and their combinations with MS risk and severity. 561 unrelated patients with bout-onset MS and 441 healthy volunteers were enrolled in the study. We observed associations of MS risk with allele MIR223*T and combination (MIR223*T + MIR146A*G/G) carriage in the entire groups and in women at Bonferroni-corrected significance level (pcorr < 0.05). Besides, MIR146A*G/G association with MS was observed in women with nominal significance (pf = 0.025). No MS associations were found in men. A more severe MS course (MSSS value > 3.5) was associated with the carriage of MIR499A*C/T and, less reliably, of MIR499A*C (pcorr = 0.006 and pcorr = 0.024, respectively) and with the carriage of combinations (MIR499A*C/T + MIR196A2*C) and (MIR499A*C + MIR196A2*C) (pcorr = 0.00078 and pcorr = 0.0059, respectively). These associations also showed gender specificity, as they were not significant in men and substantially reinforced in women. The strongest association with MS severity was observed in women for combination (MIR499A*C/T + MIR196A2*C): pcorr
= 4.43 × 10−6 and OR = 3.23 (CI: 1.99–5.26).
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