Introduction: Multiple sclerosis (MS) is a chronic progressive autoimmune disease characterised by nerve demyelination, mediated by myelin-specific Th1 autoreactive cells. Transforming growth factor β1 (TGF-β1) is a regulatory cytokine involved in MS aetiology by maintaining CD4+ cell differentiation and preventing autoimmune responses. Because of the important role of the TGF-β1 signalling pathway in MS aetiopathogenesis, we aimed to investigate the association of two DNA polymorphisms: TGFB1C[-509]T and TGFBR2G[-875]A and their combined genotypes with the risk of MS development in a cohort of Bulgarian patients. The effect of the two promoter polymorphisms on the disease onset was also assessed. Material and methods: In the study, a cohort of 183 patients with relapsing-remitting multiple sclerosis (RRMS) and 307 sex-and age-matched healthy subjects were recruited. Genotyping of the TGFB1C[-509]T (rs1800469) and TGF-BR2G[-875]A (rs3087465) polymorphisms was performed by PCR-RFLP and PIRA-PCR approaches.Results: Frequencies of the TGFB1T[-509]T genotype and TGFB1[-509]*T-allele were lower in RRMS men than in control healthy men (15.7% vs. 26.9%, 37.3% vs. 50.7%, respectively). Among males, the TGFB1T[-509]T genotype was related to a significantly reduced risk of RRMS (OR = 0.360, p = 0.05) in comparison to the TGF-B1C[-509]C genotype. Also, TGFB1[-509]*T-allele was more common in men with RRMS than in healthy men relative to the TGFB1[-509]*C-allele and was associated with a statistically significant protective effect (OR = 0.576, 95% CI: 0.341-0.974, p = 0.039). The combination of TGFB1T[-509]T/TGFB1T ]A genotypes among men was associated with a significant protective effect compared to the wild-type homozygous TGFB1C p = 0.018). No significant association between rs1800469 and rs3087465 was observed among females with and without (controls) RRMS. Conclusions: In summary, we suggest that in males, a higher TGF-β1 level determined by TGFB1T[-509]T genotype in combination with the TGFBR2G[-875]A genotype might be a protective factor against RRMS development.

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Purpose: Multiple sclerosis is the immune-mediated disorder whose etiology is not completely understood. The present study aimed to survey association between the promoter polymorphism IL18 -607C/A (rs1946518), the serum concentration of IL-18 and susceptibility to relapsing-remitting multiple sclerosis (RRMS) in Bulgarian patients Material and Methods: This case-control study includes 159 RRMS patients with disease-modifying therapy (DMT) and 162 age-sex-matched healthy volunteers. All included subjects were genotyped by ARMS-PCR while serum levels were measured by enzyme-linked immunosorbent assay (ELISA). Results: Our results revealed significant differences in the serum levels of IL-18 according to the gender, the onset of disease and the type of disease-modifying therapy. The serum levels of IL-18 are significantly higher in RRMS men compared to RRMS women and the RRMS men with late-onset of the disease (above 30 years) also demonstrated significantly increased serum levels than the women with late-onset of disease and even with healthy men. The RRMS patients treated with interferon-beta showed significantly increased IL-18 serum level than those treated with glatiramer acetate. Conclusions: Our study shows that the promoter polymorphism IL18 -607C/A is not associated with susceptibility to RRMS in Bulgarian patients as well as the serum level of the cytokine. The observed differences in the serum level of IL-18 in RRMS patients according to gender and the response to therapy could be used as a biomarker to the course of the disease.