Base Excision Repair Gene Variants Modify Multiple Sclerosis Risk: A Genetic Association Study in Central Europeans
Beata Filipek1, Anna Macieja1, Aleksandra Binda2, Elzbieta Miller3, Mariola Swiderek-Matysiak4, Mariusz Stasiolek4, Ireneusz Majsterek2, Tomasz Poplawski1
1Department of Microbiology and Pharmaceutical Biochemistry, Medical University of Lodz, 2Department of Clinical Chemistry and Biochemistry, Medical University of Lodz, 3Department of Neurological Rehabilitation, Medical University of Lodz, 4Norbert Barlicki Memorial Teaching Hospital No. 1 of the Medical University of Lodz
Objective:
We investigated whether common polymorphisms affecting DNA repair genes influence susceptibility to MS within Polish population.
Background:
MS etiology involve both genetic predisposition and environmental triggers. Oxidative damage represents a plausible mechanistic link-inflammation generates free radicals modifying cellular DNA. BER constitutes the primary defense against oxidation, making genes encoding its enzymes attractive candidates for disease association studies. Prior reports have connected BER polymorphisms to other inflammatory disorders, prompting examination of their role in MS pathogenesis.
Design/Methods:
We included 102 MS patients (predominantly relapsing-remitting subtype; EDSS 3.44±1.87) and 118 matched controls. High-throughput genotyping quantified allele frequencies at ten loci spanning seven BER genes: rs25478(XRCC1), rs1052133(OGG1), rs246079 and rs151095402(UNG), rs2307293(MBD4), rs3219472, rs3219489, and rs3219493(MUTYH), rs4135054(TDG), and rs3087404(SMUG1). We tested four inheritance models (additive, dominant, recessive, overdominant). Pairwise linkage calculations identified co-inherited haplotype blocks. For unlinked markers, multivariate regression isolated independent risk contributions while controlling for potential confounders.
Results:
Three SNPs variants elevated MS odds: (XRCC1)rs25478 (OR=2.37, 95% CI:1.44–3.91, p<0.0001), (SMUG1)rs3087404 (OR=2.80, 95% CI:1.49–5.26, p=0.0012), and (MUTYH)rs3219493 (OR=2.23, 95% CI:1.35–3.67, p=0.0018). Conversely, three conferred protection: (MBD4)rs2307293 (OR=0.42, 95% CI:0.23–0.78, p=0.006), (MUTYH)rs3219489 (OR=0.55, 95% CI:0.31–0.97, p=0.038), and (TDG)rs4135054 (OR=0.52, 95% CI:0.29–0.94, p=0.031). Within MUTYH, strong co-segregation (r²=0.90) between rs3219489 and rs3219472 justified haplotype analysis, revealing that the rare G-C combination reduced disease likelihood (score=−2.10, p=0.035). When treating remaining loci as independent predictors, adjusted models confirmed protective effects for (OGG1)rs1052133 (OR=0.57, p=0.043), (MBD4)rs2307293 (OR=0.16, p=0.010), and (TDG)rs4135054 (OR=0.38, p<0.001), while (SMUG1)rs3087404 maintained its risk association (OR=1.98, p=0.013).
Conclusions:
Our findings establish that heritable variation in BER genes shapes MS vulnerability in Central European population. The bidirectional effects-wherein specific alleles increase risk while others afford protection-suggest that individual repair capacity exists along a continuum, with extreme phenotypes conferring proportional disease susceptibility. If confirmed, such personalized approaches could ultimately complement existing immunomodulatory therapies by addressing the oxidative component of MS pathophysiology.
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