Relevance of multiple sclerosis severity genotype in predicting disease course: a real- world cohort

<h3>Objective</h3> 233 genetic loci are associated with susceptibility to multiple sclerosis (MS). Two independent pivotal severity genome-wide association studies have recently identified the first genome-wide significant single-nucleotide variant associated with disability outcomes (SNV; rs10191329) as well as a number of other suggestive loci. It is now important to understand if these findings can influence individual patient management. <h3>Methods</h3> We assessed whether these disease severity SNVs are associated with any aspects of a more detailed clinical phenotype in a well-characterized prospective cohort of 1,455 MS patients. We used logistic regression, survival analysis, and propensity score matching (PSM) to predict relevant long-term clinical outcomes. <h3>Results</h3> We were unable to detect any association between rs10191329 and a range of clinically relevant outcomes (time to Expanded Disability Status Scale milestones, age-related MS severity score, anatomical localization of relapses, annualized relapse rate). An extremes of outcome case- control analysis using PSM for genotype and potential confounders detected no association between disease severity and rs10191329. However, we were able to replicate the association of 2 suggestive SNVs (rs7289446/rs868824) with the development of fixed disability, albeit with modest effect. <h3>Interpretation</h3> Identification of SNVs are of considerable importance in understanding pathophysiological processes associated with MS severity. However, it is unlikely that individual genotyping can currently be used to guide disease management.