Abstract Details

Title Base Excision Repair Gene Variants Modify Multiple Sclerosis Risk: A Genetic Association Study in Central Europeans

Topic Multiple Sclerosis

Presentation(s) P2 - Poster Session 2 (11:45 AM-12:45 PM)

Poster/Presentation
Number 18-001

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.

Authors/Disclosures
Beata A. Filipek, MD, PhD (International Doctoral School Medical University of Lodz) PRESENTER	Dr. Filipek has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. The institution of Dr. Filipek has received research support from National Centre of Science, Poland - Preludium Bis 2019/35/O/NZ5/02270.
Anna Macieja, PhD	Ms. Macieja has nothing to disclose.
Aleksandra J. Binda	Ms. Binda has nothing to disclose.
Ryan Miller	Mr. Miller has received personal compensation for serving as an employee of Resonant. Mr. Miller has stock in Inherent Biosciences. Mr. Miller has received intellectual property interests from a discovery or technology relating to health care.
Mariola Swiderek-Matysiak	Mariola Swiderek-Matysiak has nothing to disclose.
Mariusz Stasiolek, MD	Dr. Stasiolek has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Novartis. Dr. Stasiolek has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Roche. Dr. Stasiolek has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Stasiolek has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for AstraZeneca. Dr. Stasiolek has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Stasiolek has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Roche. Dr. Stasiolek has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Biogen. Dr. Stasiolek has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Bristol Myers Squibb. Dr. Stasiolek has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for AstraZeneca. Dr. Stasiolek has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck.
Ireneusz Majsterek, PhD	Prof. Majsterek has nothing to disclose.
Tomasz Poplawski	Tomasz Poplawski has nothing to disclose.

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