**8. Conclusions**

In summary, we can conclude that many genetic and biochemical factors can be involved in the etiopathogenesis of MS. These markers could be used to evaluate the risk of MS develop‐ ment and the risk of rapid disease disability progression.

The proposed markers that have been found to be associated with MS risk or disability pro‐ gression in Central European Slovak population are summarized in **Table 3**. In our studies, we identified decreased serum level of vitamin D, allele C and genotype CC of polymor‐ phism rs6897932 in the *IL7Ra* gene, genotype Ff of rs10735810 in the *VDR* gene (only in women); HLA-alleles DRB1\*15, DRB1\*03, DQB1\*06; HLA-genotypes DRB1\*15/\*15, DQB1\*06/\*06 and HLA-haplotype DRB1\*15-DQB1\*06 as the main risk factors for MS devel‐ opment. On the contrary, allele T of rs6897932 in the *IL7Ra* gene (in individuals with geno‐ type CT and TT); HLA-alleles DRB1\*07, DRB1\*13, DQB1\*03; HLA-genotypes DRB1\*13/\*11, DQB1\*05/\*03 and HLA-haplotypes DRB1\*13-DQB1\*06 and DRB1\*11-DQB1\*03 displayed a protective effect against MS development. Genotype CC of rs6897932 in the *IL7Ra* gene and decreased serum level of vitamin D were identified as negative prognostic factors for rapid disability progression in MS, while minor allele T of rs6897932 in the *IL7Ra* gene (especially in individuals with TT genotype) was identified as a protective factor disability progression.

association with the form and severity of MS (EDSS, magnetic resonance imaging (MRI)). Allele b (G) of BsmI polymorphism of VDR has been found to be associated with MS risk in combi‐ nation with allele A (T) of ApaI polymorphism by Niino et al. [110]. However, in their study, they did not find any association of ApaI gene polymorphism with clinical form and severity of MS evaluated by the EDSS score, disease duration and MRI findings. Agliardi et al. [120] in Italy found that allele T (T) and genotype TT (TT) are protective against MS development, supported by the finding that the expression of VDR mRNA is increased four times by genotype Tt (TC) and eight times by genotype TT (TT) when compared to genotype tt (CC). The observed effect is present especially when the protective allele Tis present in the combi‐

The role of VDR gene polymorphisms is still not completely understood, and it seems to vary among different populations. For proper cell signalling to decrease the risk of MS, it is probably necessary to reach a certain level of the transcriptional activity of VDR that is also modified genetically. For proper immunoregulation, the individuals that have the genotype causing the decreased VDR protein activity can need a higher peroral vitamin D intake or higher level of sun exposure. Contrarily, in individuals with higher transcriptional activity of VDR, a lower sun exposure or vitamin D intake can be sufficient for proper immune system regulation.

The findings of our previous study in MS patients from the Central-Northern region of Slovakia have confirmed the association of FokI heterozygous genotype Ff with an increased risk of MS in women [10]. Although we found no statistically significant differences in the proportions of FokI genotypes or allele frequencies between total MS patient and the control group, we have observed significant differences in the FokI genotype distribution between women with MS and the female control group (*p* = 0.042). Our results have shown a signifi‐ cantly higher frequency of heterozygous Ff genotypes in FokI polymorphism in the female MS group (53.4%) as compared to 43.7% in the female control group (OR = 1.48, 95% CI = 1.01– 2.16). In spite of this fact, when we compared the subgroup of rapidly progressing MS patients with the subgroup of slow progressing MS patients, allele and genotype counts were not significantly different between them (allele f: 34.5 vs. 43.3%, allele F: 65.5 vs. 56.7%, genotype ff: 10.3 vs. 13.4%, genotype Ff: 48.3 vs. 59.8%). Since we have not shown any significant association between FokI VDR gene polymorphism and the rate of disease disability progres‐ sion in our cohort of Slovak MS patients, we observed a trend of higher frequency of homo‐ zygotes FF to be 41.4% in MS patients with rapid progression of disease as compared to 26.8% in slow progressing MS patients (OR = 1.93, 95% CI=0.94–3.94) with a marginal level of significance (*p* = 0.071). From the results of our study, it seems that contributions from genetic and allelic variants of FokI VDR gene polymorphism have only a small impact in a disease as

complex as MS, andits role in the etiopathogenesis of MS still remains controversial.

ment and the risk of rapid disease disability progression.

In summary, we can conclude that many genetic and biochemical factors can be involved in the etiopathogenesis of MS. These markers could be used to evaluate the risk of MS develop‐

nation with HLA-DRB1\*15 allele.

16 Trending Topics in Multiple Sclerosis

**8. Conclusions**


**Table 3.** The proposed markers associated with the MS risk or disability progression in Slovaks [10, 41, 65].

From the results of our study, we conclude that rs6897932 of the *IL7Ra*gene, rs10735810 in the *VDR* gene, HLA-DR and DQ genotypes, as well as serum level of vitamin D may be the important markers that could be used as part of a panel of markers to evaluate the risk of MS development and disability progression. The relevance of these markers identified in our study should be verified in larger groups of individuals not only in Slovakia but also in other different populations. The relevant positive or negative prognostic genetic or biochemical markers can improve the diagnostic and therapeutic procedure and can help to minimize neurological damage in predisposed individuals.
