Unraveling Genetic Insights into Multiple Sclerosis Severity: What We Know So Far

Multiple sclerosis (MS) is a complex immune-mediated neurodegenerative disease characterized by an unpredictable course, with patients exhibiting various levels of disability progression over time. Recent advancements in genomics have identified several genetic loci associated with MS susceptibility, but their role in disease severity remains unclear. In a landmark study published in Annals of Neurology (2023), Kreft et al. sought to explore the potential of genetic markers to predict MS severity and its clinical progression in a real-world cohort of patients.

Understanding MS Severity and the Role of Genetics
MS is a chronic neuroinflammatory disease, with both early inflammatory and later neurodegenerative stages. Despite the availability of numerous disease-modifying treatments (DMTs) aimed at controlling neuroinflammation, many individuals with MS (pwMS) eventually develop permanent disability. Genetic predisposition is known to play a significant role in MS susceptibility, with over 233 loci already associated with the disease. However, the identification of genetic factors driving disease severity has been challenging.

The discovery of the single-nucleotide variant (SNV) rs10191329A, associated with faster progression toward disability, provided a promising lead. This variant, identified through genome-wide association studies (GWAS), held the potential to influence clinical management. Kreft et al. aimed to assess whether this and other SNVs associated with MS severity could predict long-term clinical outcomes in a large, well-characterized cohort.

Study Design and Methodology
The study cohort comprised 1,455 patients from the South Wales MS Registry, which had been collecting longitudinal data since 1985. Participants were genotyped using high-resolution methods, and key MS progression metrics—such as time to disability milestones (Expanded Disability Status Scale or EDSS) and annualized relapse rates—were analyzed. The team employed statistical methods like logistic regression, survival analysis, and propensity score matching to assess the relationship between SNVs and clinical outcomes.

One of the primary aims was to replicate the findings of earlier GWAS studies, particularly regarding rs10191329A, in a real-world setting. The study also evaluated other candidate SNVs, such as rs7289446G and rs868824C, for their potential to predict disability progression.

Key Findings: Limited Predictive Power of SNVs
Despite the earlier identification of rs10191329A as a candidate for influencing MS severity, the study found no significant association between this variant and key clinical outcomes. Kreft et al. were unable to replicate the original GWAS findings for rs10191329A, either in predicting time to disability milestones or influencing age-related MS severity score (ARMSS). In both relapsing-remitting and progressive forms of MS, the presence of rs10191329A did not correlate with increased disability or earlier onset of progressive disease.

Interestingly, the study did validate two other suggestive SNVs—rs7289446G and rs868824C—as being modestly associated with the development of fixed disability. However, the effect sizes of these associations were small, and the clinical relevance remains uncertain.

Role of Polygenic Risk Scores
The research team also explored the utility of polygenic risk scores (PRS) based on MS susceptibility loci. Despite considerable progress in identifying these genetic markers, the PRS derived from MS susceptibility genes showed no association with long-term disability outcomes. This suggests that the genetic factors driving MS susceptibility may differ from those influencing disease progression and severity.

In contrast, the study did replicate the previously established association of the HLA-DRB1*1501 allele with younger age at MS onset. However, this allele was not predictive of long-term disability or disease course.

Implications for Clinical Practice and Future Research
The findings of Kreft et al. highlight the complexity of MS progression and the challenges of using genetic markers to predict disease severity in clinical practice. While the discovery of genetic variants associated with MS severity remains crucial for understanding the underlying pathophysiological processes, the current study underscores the need for replication in diverse, real-world cohorts.

The authors concluded that individual genotyping for SNVs such as rs10191329A is unlikely to be useful in guiding MS management at present. The study emphasizes the importance of independent replication of GWAS findings and calls for further research into the biological mechanisms underlying MS severity, particularly focusing on neurodegeneration, which may be distinct from the inflammatory pathways associated with early disease.

Conclusion
Kreft et al.'s study is an important contribution to the growing body of research on the genetic basis of MS severity. Although the study could not confirm the utility of rs10191329A as a prognostic tool, it validated other suggestive SNVs and reinforced the role of HLA-DRB1*1501 in influencing disease onset. As genomic technologies continue to evolve, further large-scale studies will be essential to unlock the full potential of genetics in predicting MS progression and improving patient care.

References:
Kreft, K. L., Uzochukwu, E., Loveless, S., Willis, M., Wynford‐Thomas, R., Harding, K. E., ... & Robertson, N. P. (2024). Relevance of Multiple Sclerosis Severity Genotype in Predicting Disease Course: A Real‐World Cohort. Annals of Neurology, 95(3), 459-470.