Relevance of Multiple Sclerosis Severity Genotype in Predicting Disease Course: A Real-World Cohort

Abstract

Objective: Currently, 233 genetic loci are known to be associated with susceptibility to multiple sclerosis (MS). Two independent pivotal severity genome-wide association studies recently found the first genome-wide significant single-nucleotide variant (SNV; rs10191329^A ) and several other suggestive loci associated with overall disability outcomes. It is now important to understand if these findings can influence individual patient management.

Methods: We assessed whether these progression SNVs are associated with detailed clinical phenotypes in a well-characterized prospective cohort of 1,455 MS patients. We used logistic regression, survival analysis, and propensity score matching to predict relevant long-term clinical outcomes.

Results: We were unable to detect any association between rs10191329^A and a range of clinically relevant outcomes (eg, time to Expanded Disability Status Scale milestones, age-related MS severity score, anatomical localization at onset or during subsequent relapses, annualized relapse rate). In addition, an extremes of outcome case-control analysis using a propensity score matching for genotype detected no association between disease severity and rs10191329^A . However, we were able to replicate the association of two suggestive SNVs (rs7289446^G and rs868824^C ) with the development of fixed disability, albeit with modest effect sizes, and the association of HLA-DRB1*1501 with age at onset.

Interpretation: Identification of rs10191329^A and other suggestive SNVs are of considerable importance in understanding pathophysiological processes associated with MS severity. However, it is unlikely that individual genotyping can currently be used in a clinical setting to guide disease management. This study shows the importance of independent replication of genome-wide association studies associated with disease progression in neurodegenerative disorders. ANN NEUROL 2024;95:459-470.