Background Vitamin D-binding protein (VDBP), encoded by the GC gene, governs vitamin D transport and bioavailability. Two common GC SNPs, rs7041 and rs4588, influence serum vitamin D and may modify multiple sclerosis (MS) course and response to disease-modifying therapies (DMTs).

Aim To determine whether rs7041 and rs4588 predict two-year treatment outcomes in Latvian MS patients.

Methods We genotyped rs7041/rs4588 (restriction analysis) in 296 MS patients; 230 received 342 DMT courses. Clinical response was defined as a change in Expanded Disability Status Scale (EDSS) and the attainment of “no evidence of disease activity” (NEDA) over 24 months. Associations were analysed with χ²/Fisher tests and multivariate logistic regression.

Results and Discussion

Our analysis revealed associations between GC gene variants and treatment outcomes in Latvian MS patients. The rs7041 GG genotype was linked to reduced mitoxantrone efficacy (OR 2.3, p = 0.02) and a lower chance of achieving NEDA in the first year (OR 1.9, p = 0.04). Conversely, rs4588 CC homozygotes showed a higher likelihood of sustained NEDA by year two (OR 2.1, p = 0.03). Neither SNP significantly influenced EDSS progression, and no relevant associations were found with other DMTs. These results indicate that GC polymorphisms may act as markers of therapeutic response, particularly regarding mitoxantrone and NEDA. Further studies are needed to explore the underlying biological mechanisms.

Conclusions
GC variants rs7041 and rs4588 affect MS treatment outcomes in Latvians. rs7041 GG is associated with a reduced benefit from mitoxantrone, while rs4588 CC correlates with more favorable NEDA results. These findings support the potential for genotype-guided therapy, pending further validation.

Funding UL project 1.1.1.2/VIAA/4/20/718; ERDF 1.1.1.1/16/A/016; UL Foundation (MikroTik) 40021.