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Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
Increased Disability Progression in rs10191329AA Carriers with Multiple Sclerosis Is Preceded by Neurofilament Light
Maria Protopapa1, Falk Steffen1, Muriel Schraad1
1Department of Neurology, Research Center for Immunotherapy (FZI) and Focus Program Translational Neuroscience (FTN), Rhine-Main Neuroscience Network (rmn2), University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
Objective:
We examined the impact of the rs10191329 genetic risk variant on neuroaxonal damage as measured by serum neurofilament light chain (sNfL) levels, and disability progression in people with multiple sclerosis (pwMS).
Methods:
In a cohort of pwMS (n = 740), 658 participants were prospectively monitored every 2 years for less than a decade while 82 of 740 pwMS were monitored retrospectively for up to 40 years. We investigated associations between rs10191329 variants and clinical outcome, including Expanded Disability Status Scale (EDSS), disability accrual (defined by EDSS-increase of at least 1.5 for patients starting at EDSS 0, at least 1.0 EDSS-points for patients with an initial EDSS between 1 and 4.5 and at least 0.5 points for patients starting with an EDSS equal or greater than 5) and progression to secondary progressive MS (SPMS). Clinical outcomes were analyzed using Kaplan-Meier and Cox proportional hazards analyses. Disability accumulation over time was depicted using a generalized mixed-effect model. Single-molecule array was used to assess sNfL levels.
Results:
Homozygous, heterozygous, and non-carriers of the rs10191329 risk variant displayed comparable sNfL levels indicating similar neuroaxonal damage at the time of diagnosis. Importantly, in homozygous carriers we found highest sNfL levels in follow-up visits preceding elevated disease progression later in the disease course, a steeper increase in overall disability measures and higher probability of SPMS development.
Interpretation:
These findings highlight how genetic variants may serve as new biomarkers for disease progression and can be used for personalized medicine and risk assessment in MS. ANN NEUROL 2025;97:596-605.
