Increased Disability Progression in rs10191329AA Carriers with Multiple Sclerosis Is Preceded by Neurofilament Light Chain Elevations

Abstract

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.

FIGURE 1

Despite no difference in people at risk for MS and at diagnosis, pwMS homogyzgous carriers of the risk allele exhibit increased neurofilament already early in the disease course, followed by increased disease severity. Box plots presenting sNfL levels in (A) asymptomatic first‐degree relatives of persons with MS (no significant differences) and (B) in pwMS at MS*0 and MS*1, with Kruskal–Wallis tests for each time point and post‐hoc tests with Dunn's correction for multiple comparisons. At MS*0 we observed no significant differences (p = 0.227). At MS*1 homozygous carriers had significantly increased sNfL levels compared to non‐carriers (p = 0.005) and heterozygous carriers (p = 0.005). Further ANCOVAs were performed accounting for confounders such as age, BMI, EDSS, or Gd‐enhancing lesions (for details see Table 2). (C) Box plot illustrates the course of EDSS in the early cohort with significantly increased values in homozygous carriers at MS*2 (p = 0.005, compared with non‐carrier; p = 0.009, compared with heterozygous carrier; Kruskal–Wallis tests with Dunn's multiple comparisons correction). A jitter was applied to the data points for visualization purposes. (D) A bar chart is shown with the respective percentages of patients with and without disability accrual at MS*2 relative to MS*1 (p < 0.001, Fishers exact test two‐sided; significant differences between homozygous carrier and both non‐carrier and heterozygous carrier confirmed by multiple z‐tests of two proportions). [Color figure can be viewed at www.annalsofneurology.org]

Figure 2

Evidence for increased long‐term disability in carriers of the severity risk allele. (A) A box plot illustrates the trajectory of EDSS. Notably, EDSS exhibited a statistically significant increase between years 5 and 10 in homozygous carriers compared with non‐carriers (p = 0.047), and beyond the 10‐year mark compared with both non‐carriers (p < 0.001) and heterozygous carriers (p = 0.012, Kruskal–Wallis tests with Dunn's multiple comparisons correction). A jitter was applied to the data points for visualization purposes. (B) Evolution of group‐specific EDSS scores over the duration of the symptoms (time since first manifestation). Individually observed EDSS scores are denoted by squares, triangles, and circles, while regression lines and the corresponding standard error of the means, represented as surrounding areas, are derived from a linear mixed‐effects model demonstrating a significant interaction term between disease duration and homozygous genotype (β = 0.11 [0.06–0.16], p < 0.001). Disease duration, genotype, age at onset, time spent in a specific DMT group, and sex were incorporated as covariates (Table 3). Genotype groups are delineated by different colors (blue: non‐carrier; orange: heterozygous; green: homozygous). A jitter was applied to the data points for visualization purposes. (C, D) Kaplan–Meier analysis revealed (C) differences in the survival proportion (log‐rank p = 0.003), which was due to an elevated risk of attaining an EDSS score of ≥4.5 in rs10191329^AA (p = 0.002 compared with rs10191329^CC; Bonferroni‐adjusted); additionally, there were (D) differences regarding the survival‐proportion (log‐rank p < 0.001) due to a heightened risk of transitioning to SPMS in homozygous carriers (p = 0.002 compared with rs10191329^CC; p = 0.033 compared with rs10191329^CA; Bonferroni‐adjusted). These analyses were further validated using Cox proportional hazard analyses after inclusion of several covariates (Tables 4 and 5). [Color figure can be viewed at www.annalsofneurology.org]