Department of Molecular Biology, Immunology, and Medical Genetics, Medical Faculty Trakia University, Stara Zagora, Bulgaria.
Department of Neurology, Faculty of Medicine, Medical University of Plovdiv, Bulgaria.
Folia Neuropathol. 2020;58(4):307-316. doi: 10.5114/fn.2020.102433.
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.
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.
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.
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.
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β1（TGF-β1）是一种调节细胞因子，通过维持 CD4+细胞分化和防止自身免疫反应参与 MS 的发病机制。鉴于 TGF-β1 信号通路在 MS 发病机制中的重要作用，我们旨在研究两个 DNA 多态性：TGFB1C[-509]T 和 TGFBR2G[-875]A 及其组合基因型与保加利亚患者队列中 MS 发病风险的相关性。还评估了两种启动子多态性对疾病发病的影响。
在这项研究中，我们招募了 183 名复发性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对照者。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。
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组健康男性（15.7%比 26.9%，37.3%比 50.7%）。在男性中，与 TGFB1C[-509]C 基因型相比，TGFB1T[-509]T 基因型与 RRMS 的风险显著降低相关（OR=0.360，95%CI：0.126-1.028，p=0.05）。此外，与 TGFB1[-509]*C-等位基因相比，TGFB1[-509]*T-等位基因在 RRMS 男性中更为常见，与统计学显著的保护作用相关（OR=0.576，95%CI：0.341-0.974，p=0.039）。与野生型纯合子 TGFB1C[-509]C 和 TGFBR2G[-875]G 基因型相比，男性中 TGFB1T[-509]T/TGFB1T[-509]C 和 TGFBR2G[-875]A 基因型的组合与显著的保护作用相关（OR=0.268，95%CI：0.088-0.818，p=0.018）。在患有和不患有 RRMS（对照组）的女性中，均未观察到 rs1800469 与 rs3087465 之间存在显著相关性。
总之，我们认为在男性中，TGFB1T[-509]T 基因型与 TGFBR2G[-875]A 基因型相结合决定的较高 TGF-β1 水平可能是 RRMS 发病的保护因素。
