Genetic insights into multiple sclerosis: exploring mitochondrial DNA and nuclear POLG gene variation in a Polish single-center RRMS cohort

AIM OF THE STUDY: To evaluate the contribution of mitochondrial DNA (mtDNA) variation and four POLG mutations to disease susceptibility and course in Polish patients with relapsing-remitting multiple sclerosis (RRMS). CLINICAL RATIONALE FOR THE STUDY: Mitochondrial dysfunction is increasingly implicated in the pathogenesis of multiple sclerosis (MS), yet its precise role remains unclear. Determining the impact of mtDNA variation and POLG mutations may improve understanding of factors influencing disease onset and progression. MATERIAL AND METHODS: Whole mtDNA was sequenced in 100 RRMS patients using next-generation sequencing and compared with previously generated mtDNA data from 212 Polish individuals without MS. The presence of pathogenic variants, distribution of haplogroups, rare variants, and heteroplasmy were assessed. Absolute mtDNA copy number was measured by real-time PCR. Additionally, RRMS patients were screened for four common POLG mutations (p.Gly268Ala, p.Ala467Thr, p.Pro587Leu, and p.Trp748Ser). RESULTS: No pathogenic mtDNA variants or any of the four screened POLG variants were detected. No significant associations were found between major mtDNA haplogroups, copy number, heteroplasmy, or rare variants and MS risk or progression. Exploratory analyses identified nominal associations between several mtDNA variants and relapse occurrence, disability level, age at symptom onset, and sex in the RRMS cohort. CONCLUSIONS AND CLINICAL IMPLICATIONS: Pathogenic mtDNA variants, major haplogroups, mtDNA copy number, rare variant burden, and the four screened POLG variants do not appear to play a major role in RRMS susceptibility or clinical course in the analyzed cohort. Several associations involving individual mtDNA variants were identified, but these findings are exploratory and require independent replication in larger cohorts before their biological or clinical relevance can be established.