The HLA paradox across populations in multiple sclerosis progression: a systematic review

Multiple sclerosis (MS) exhibits heterogeneity in disease courses. Although HLA DRB1*15:01 represents the strongest genetic risk factor for MS susceptibility, conferring approximately threefold increased risk, whether this allele similarly influences disease progression remains contentious.

This systematic review was conducted to clarify the relationship between HLA polymorphisms and the course of multiple sclerosis from inception through November 2025. A three-level random effects meta-analysis was used to account for statistical non-independence. Study quality was evaluated using Q GENIE criteria.

In total, 56 eligible studies were selected, comprising 22,145 participants; 35 studies contributed 276 effect sizes to quantitative synthesis. The pooled estimate indicated a modest overall association between HLA variants and MS progression (Odds Ratio (OR) 1.30, 95% CI 1.09 to 1.55, p = 0.003). HLA DRB1*15 showed no significant association with disease progression (OR 1.10, 95% CI 0.79 to 1.51, p = 0.57). Exploratory subgroup analysis revealed significant regional heterogeneity (QM = 10.48, p = 0.033): Asian (OR 1.70, p < 0.001) and North American (OR 1.95, p < 0.001) studies suggested significant effects, whereas European studies showed no effect (OR 1.02, p = 0.92). Three alleles demonstrated significant adverse associations: HLA DRB1*04 (OR 1.79, 95% CI 1.33 to 2.42), HLA DRB1*09 (OR 4.21, 95% CI 1.93 to 9.18), and HLA DRB1*03 (OR 1.44, 95% CI 1.01 to 2.05).

This systematic review suggests that multiple sclerosis susceptibility and progression appear governed by distinct genetic architectures.