Genetic Influences on Disease-Modifying Therapy Response in Multiple Sclerosis: Current Insights and Future Directions

Abstract

Multiple sclerosis (MS) is a clinically and biologically heterogeneous, immune-mediated disease of the central nervous system, with substantial interindividual variability in disease course and response to disease-modifying therapies (DMTs). Over the past three decades, the MS therapeutic landscape has expanded considerably; however, treatment selection and switching remain guided primarily by clinical phenotype and imaging findings rather than molecular predictors of response. Despite extensive clinical trial evidence, prospectively identifying responders and non-responders to specific DMTs remains challenging. Genetic variability appears to influence differences in treatment efficacy, tolerability, and long-term outcomes in people with MS. Numerous candidate pharmacogenomic variants have been reported across interferon-beta, glatiramer acetate, oral agents, and monoclonal antibodies; nevertheless, replication has been inconsistent, effect sizes are modest, and no genetic marker has yet been clinically validated for routine use. Consequently, pharmacogenomics is largely absent from current MS treatment algorithms. This review critically evaluates the existing pharmacogenomic literature across approved DMTs, highlighting reproducible findings, methodological limitations, and gaps that hinder clinical translation. We further discuss requirements for integrating pharmacogenomic markers into routine practice, emphasizing the need for large, multiethnic cohorts, standardized response definitions, and functional validation. Overall, these insights underscore both the potential and current limitations of pharmacogenomics in advancing precision medicine for MS.