Filipek Beata, Macieja Anna, Binda Aleksandra, Miller Elzbieta, Swiderek-Matysiak Mariola, Stasiolek Mariusz, Stela Maksymilian, Majsterek Ireneusz, Poplawski Tomasz
Department of Microbiology and Pharmaceutical Biochemistry, Medical University of Lodz, Mazowiecka 5, 92-215 Lodz, Poland.
Department of Neurology, Medical University of Lodz, Kopcinskiego 22, 90-153 Lodz, Poland.
Int J Mol Sci. 2025 Jul 10;26(14):6612. doi: 10.3390/ijms26146612.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system characterized by demyelination and neurodegeneration. While its etiology remains unclear, both genetic and environmental factors, including oxidative stress, have been implicated in the development of the disease. The base excision repair (BER) pathway plays a critical role in repairing oxidative DNA damage. This study investigated the association between polymorphisms in BER-related genes and MS susceptibility in a Central European population. Ten SNPs across seven BER genes were genotyped in 102 patients with MS and 118 healthy controls. Six SNPs were significantly associated with MS. Increased risk was observed for rs25478 in XRCC1 (OR = 2.37, 95% CI: 1.44-3.91, < 0.0001), rs3087404 in SMUG1 (OR = 2.80, 95% CI: 1.49-5.26, = 0.0012), and rs3219493 in MUTYH (OR = 2.23, 95% CI: 1.35-3.67, = 0.0018). Conversely, reduced risk was associated with rs2307293 in MBD4 (OR = 0.42, 95% CI: 0.23-0.78, = 0.006), rs3219489 in MUTYH (OR = 0.55, 95% CI: 0.31-0.97, = 0.038), and rs4135054 in TDG (OR = 0.52, 95% CI: 0.29-0.94, = 0.031). Haplotype analysis was performed for SNPs in strong linkage disequilibrium. Only rs3219489 and rs3219472 within the MUTYH gene showed strong LD (r = 0.90), justifying haplotype-based analysis. Among four inferred haplotypes, the rare G-C haplotype was significantly associated with reduced MS risk (Score = -2.10, = 0.035), suggesting a protective effect of this allele combination. Other SNPs not in LD were analyzed using a multivariable logistic regression model. Significant associations with decreased MS risk were found for rs1052133 in OGG1 (OR = 0.57, = 0.043), rs2307293 in MBD4 (OR = 0.16, = 0.010), and rs4135054 in TDG (OR = 0.38, < 0.001), while rs3087404 in SMUG1 increased MS risk (OR = 1.98, = 0.013). These results suggest that genetic variation in BER genes, including both single SNP effects and haplotypes, contributes to MS susceptibility. Further studies are warranted to explore the functional consequences of these variants and validate findings in larger, independent cohorts.
多发性硬化症（MS）是一种中枢神经系统的慢性炎症性疾病，其特征为脱髓鞘和神经退行性变。虽然其病因尚不清楚，但遗传和环境因素，包括氧化应激，都被认为与该疾病的发生有关。碱基切除修复（BER）途径在修复氧化性DNA损伤中起关键作用。本研究调查了中欧人群中BER相关基因多态性与MS易感性之间的关联。对102例MS患者和118例健康对照者的7个BER基因中的10个单核苷酸多态性（SNP）进行了基因分型。6个SNP与MS显著相关。观察到XRCC1基因中的rs25478风险增加（比值比[OR]=2.37，95%置信区间[CI]：1.44-3.91，P<0.0001），SMUG1基因中的rs3087404风险增加（OR=2.80，95%CI：1.49-5.26，P=0.0012），MUTYH基因中的rs3219493风险增加（OR=2.23，95%CI：1.35-3.67，P=0.0018）。相反，MBD4基因中的rs2307293风险降低（OR=0.42，95%CI：0.23-0.78，P=0.006），MUTYH基因中的rs3219489风险降低（OR=0.55，95%CI：0.31-0.97，P=0.038），TDG基因中的rs4135054风险降低（OR=0.52，95%CI：0.29-0.94，P=0.031）。对处于强连锁不平衡的SNP进行了单倍型分析。仅MUTYH基因中的rs3219489和rs3219472显示出强连锁不平衡（r=0.90），这证明了基于单倍型的分析是合理的。在四种推断的单倍型中，罕见的G-C单倍型与MS风险降低显著相关（得分=-2.10，P=0.035），表明这种等位基因组合具有保护作用。对其他不处于连锁不平衡的SNP使用多变量逻辑回归模型进行分析。发现OGG1基因中的rs1052133与MS风险降低显著相关（OR=0.57，P=0.043），MBD4基因中的rs2307293与MS风险降低显著相关（OR=0.16，P=0.010），TDG基因中的rs4135054与MS风险降低显著相关（OR=0.38，P<0.001），而SMUG1基因中的rs3087404增加了MS风险（OR=1.98，P=0.013）。这些结果表明，BER基因中的遗传变异，包括单个SNP效应和单倍型，都与MS易感性有关。有必要进一步研究这些变异的功能后果，并在更大的独立队列中验证研究结果。
