Introduction
Multiple sclerosis (MS) is a chronic progressive autoimmune disease characterised by nerve demyelination, mediated by myelin-specific Th1 autoreactive cells. Transforming growth factor 1 (TGF-1) 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-1 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 TGFBR2G[-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, 95% CI: 0.126-1.028, p = 0.05) in comparison to the TGFB1C[-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[-509]C and TGFBR2G[-875]A genotypes among men was associated with a significant protective effect compared to the wild-type homozygous TGFB1C[-509]C and TGFBR2G[-875]G genotypes (OR = 0.268, 95% CI: 0.088-0.818, 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-1 level determined by TGFB1T[-509]T genotype in combination with the TGFBR2G[-875]A genotype might be a protective factor against RRMS development.



中文翻译：

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转化生长因子 β1 (TGFB1) 和 TGF-β1 受体 II (TGFBR2) 基因启动子多态性与复发缓解型多发性硬化症之间的联系

简介
多发性硬化症 (MS) 是一种慢性进行性自身免疫性疾病，其特征是神经脱髓鞘，由髓鞘特异性 Th1 自身反应性细胞介导。转化生长因子 1 (TGF-1) 是一种调节性细胞因子，通过维持 CD4+ 细胞分化和防止自身免疫反应参与 MS 病因。由于 TGF-1 信号通路在 MS 发病机制中的重要作用，我们旨在研究两种 DNA 多态性的关联：TGFB1C[-509]T 和 TGFBR2G[-875]A 及其组合基因型与 MS 风险的关系在一组保加利亚患者中的发展。还评估了两种启动子多态性对疾病发作的影响。

材料与方法
在这项研究中，招募了 183 名复发缓解型多发性硬化症 (RRMS) 患者和 307 名性别和年龄匹配的健康受试者。通过 PCR-RFLP 和 PIRA-PCR 方法对 TGFB1C[-509]T (rs1800469) 和 TGFBR2G[-875]A (rs3087465) 多态性进行基因分型。

结果
RRMS 男性中 TGFB1T[-509]T 基因型和 TGFB1[-509]*T 等位基因的频率低于对照健康男性（分别为 15.7% 与 26.9%、37.3% 与 50.7%）。在男性中，与 TGFB1C[-509]C 基因型相比，TGFB1T[-509]T 基因型与显着降低的 RRMS 风险相关（OR = 0.360，95% CI：0.126-1.028，p = 0.05）。此外，相对于 TGFB1[-509]*C 等位基因，TGFB1[-509]*T 等位基因在 RRMS 男性中比在健康男性中更常见，并且与统计学上显着的保护作用相关（OR = 0.576，95% CI：0.341-0.974，p = 0.039）。与野生型纯合 TGFB1C[-509]C 和 TGFBR2G[- 875]G 基因型（OR = 0.268，95% CI：0.088-0.818，p = 0.018）。

结论
总之，我们认为在男性中，由 TGFB1T[-509]T 基因型结合 TGFBR2G[-875]A 基因型决定的较高 TGF-1 水平可能是防止 RRMS 发展的保护因素。