Polymorphisms in Base Excision Repair Genes and Association with Multiple Sclerosis in a Pilot Study on a Central European Population

Abstract

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, p < 0.0001), rs3087404 in SMUG1 (OR = 2.80, 95% CI: 1.49-5.26, p = 0.0012), and rs3219493 in MUTYH (OR = 2.23, 95% CI: 1.35-3.67, p = 0.0018). Conversely, reduced risk was associated with rs2307293 in MBD4 (OR = 0.42, 95% CI: 0.23-0.78, p = 0.006), rs3219489 in MUTYH (OR = 0.55, 95% CI: 0.31-0.97, p = 0.038), and rs4135054 in TDG (OR = 0.52, 95% CI: 0.29-0.94, p = 0.031). Haplotype analysis was performed for SNPs in strong linkage disequilibrium. Only rs3219489 and rs3219472 within the MUTYH gene showed strong LD (r² = 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, p = 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, p = 0.043), rs2307293 in MBD4 (OR = 0.16, p = 0.010), and rs4135054 in TDG (OR = 0.38, p < 0.001), while rs3087404 in SMUG1 increased MS risk (OR = 1.98, p = 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.

Keywords: base excision repair; gene polymorphisms; multiple sclerosis.

Figure 1

Forest plot illustrating odds ratios (ORs) with 95% confidence intervals (CIs) for six single-nucleotide polymorphisms (SNPs) in base excision repair (BER) genes that showed statistically significant associations with multiple sclerosis (MS). Three SNPs—rs25478 in XRCC1, rs3087404 in SMUG1, and rs3219493 in MUTYH—were associated with an increased risk of MS (OR > 1), while three others—rs2307293 in MBD4, rs3219489 in MUTYH, and rs4135054 in TDG—were associated with a decreased risk of MS (OR < 1). The horizontal bars represent 95% confidence intervals. The red vertical dashed line indicates an odds ratio of 1.0 (no association). Odds ratios are plotted on a logarithmic scale. Only SNPs with p-values < 0.05 after Bonferroni correction are included.