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The HLA paradox across populations in multiple sclerosis progression: a systematic review
Zhila Maghbooli1, Erfan Nasir2, Fatemeh Mahdavinasab2
1Multiple Sclerosis Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran. zhilayas@gmail.com.
Background:
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.
Methods:
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.
Results:
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).
Conclusion:
This systematic review suggests that multiple sclerosis susceptibility and progression appear governed by distinct genetic architectures.
Insights
Genetic factors influencing multiple sclerosis (MS) progression differ from those affecting susceptibility. While HLA DRB1*15:01 is a key risk factor for MS, this review found no significant link to disease progression.
Area of Science:
- Immunogenetics
- Neuroimmunology
- Human Genetics
Background:
- Multiple sclerosis (MS) displays variable disease courses.
- The HLA DRB1*15:01 allele is the primary genetic risk factor for MS susceptibility.
- The role of HLA polymorphisms in MS progression remains unclear.
Purpose of the Study:
- To systematically review and meta-analyze the association between HLA polymorphisms and multiple sclerosis progression.
- To clarify the genetic architecture influencing MS susceptibility versus progression.
Main Methods:
- Systematic review and meta-analysis of eligible studies up to November 2025.
- Three-level random effects model to address statistical non-independence.
- Study quality assessed using Q GENIE criteria.
Main Results:
- A modest overall association between HLA variants and MS progression was found (OR 1.30).
- HLA DRB1*15 showed no significant association with disease progression (OR 1.10).
- Significant regional heterogeneity observed; Asian and North American studies showed effects, European studies did not.
- HLA DRB1*04, HLA DRB1*09, and HLA DRB1*03 alleles were associated with adverse progression.
Conclusions:
- MS susceptibility and progression are influenced by distinct genetic factors.
- The genetic basis for MS initiation differs from that driving its advancement.
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