Background The ubiquitin–proteasome system modulates immune signalling; under inflammatory stimuli, standard 20S proteasomes switch to immunoproteasomes incorporating PSMB8 (LMP7) and PSMB9 (LMP2). Proteasome dysfunction is implicated in multiple sclerosis (MS) and may influence the response to disease-modifying therapies (DMTs).

Aim To test whether PSMB8 and PSMB9 single-nucleotide polymorphisms (SNPs) associate with two-year clinical outcomes in Latvian MS patients.

Methods We analysed rs2071543, rs9357155 (PSMB8) and rs17587 (PSMB9) genotypes, previously generated by PCR-RFLP, in 230 patients (342 DMT courses) from a national MS registry. Therapy response was defined as the annual change in Expanded Disability Status Scale (EDSS) and the attainment of “no evidence of disease activity” (NEDA) over 24 months. Associations with glatiramer acetate (GA) and other DMTs were evaluated using χ² and logistic regression (α = 0.05).

Results and Discussion GA-treated patients carrying rare-allele genotypes CT+TT of PSMB8 rs2071543, common-allele homozygote CC of PSMB8 rs9357155, or common-allele homozygote GG of PSMB9 rs17587 exhibited significantly greater EDSS worsening during the first treatment year (p ≤ 0.037). In year 2, the risk pattern shifted: carriers of rare alleles (AA+GA) of PSMB9 rs17587 showed poorer EDSS outcomes (p = 0.028) than GG homozygotes, suggesting time-dependent genotype effects. No significant associations were observed for other DMT classes, underscoring a GA-specific interaction. This data suggests that genetic variation in immunoproteasome genes may influence GA treatment response in a time-dependent manner, possibly due to shifting immune mechanisms over the course of therapy.

Conclusion Polymorphisms in PSMB8 and PSMB9 modulate the clinical response to glatiramer acetate in Latvian MS patients and merit validation as pharmacogenetic markers for personalised DMT selection.

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