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

Kreft, Karim L., Uzochukwu, Emeka, Loveless, Sam ORCID:, Willis, Mark ORCID:, Wynford-Thomas, Ray, Harding, Katharine E., Holmans, Peter ORCID:, Lawton, Michael, Tallantyre, Emma C. ORCID: and Robertson, Neil P. ORCID: 2024. Relevance of multiple sclerosis severity genotype in predicting disease course: A real-world cohort. Annals of Neurology 95 (3) , pp. 459-470. 10.1002/ana.26831

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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, rs10191329A) 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 1455 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 rs10191329A and a range of clinically relevant outcomes (e.g. time to EDSS 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 rs10191329A. However, we were able to replicate association of two suggestive SNVs (rs7289446G and rs868824C) with development of fixed disability, albeit with modest effect sizes, and the association of HLA-DRB1*1501 with age at onset. Interpretation: Identification of rs10191329A 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher: Wiley
ISSN: 1531-8249
Date of First Compliant Deposit: 22 November 2023
Date of Acceptance: 6 November 2023
Last Modified: 04 Apr 2024 14:05

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