2025 American Academy of Neurology Abstract Website

Objective:

To investigate whether the rs10191329 variant is associated with retinal layer thinning in relapsing multiple sclerosis (MS).

Background:

The minor allele of the genetic variant rs10191329 in the DYSF–ZNF638 locus, which is implicated in CNS resilience rather than immune-mediated pathology, has been associated with faster disability progression in MS. Retinal layer thinning measured by optical coherence tomography (OCT) is an established biomarker of neuroaxonal damage.

Design/Methods:

From a prospective observational study, we included patients with RMS and ≥2 OCT scans excluding eyes with optic neuritis during the observation period.

DNA samples were genotyped on an Illumina Infinium Global Screening Array-24 (GSA v3.0+MD) imputing individual variants onto the Haplotype Reference Consortium panel (Release 1.1) using Minimac4 (V1.0.2).

We used a multivariate linear regression model with mean annualized rates of retinal layer thinning (%/year) in peripapillary retinal nerve fiber layer (aLpRNFL) and macular ganglion-cell-and-inner-plexiform-layer (aLGCIPL) thinning as the dependent variable and rs10191329 risk allele number (rs10191329*A) as the independent variableadjusting for age, sex and 10 ancestry components.

Results:

We included 208 RMS patients (mean age 30.5 years [SD 7.9], 74.1% female, median EDSS 2.0 [range 0-6.5], median observation period 25 months [range 12-105], median number of OCT scans 3 [2-6]).

We found that the risk allele of rs10191329 was associated with higher rates of retinal thinning (estimate 0.119 [standard error 0.056], one-sided p <0.001).

Each rs10191329*A allele was associated with an increase of aLpRNFL by 0.10%/year (95% confidence interval [CI] 0.05-0.19, p<0.001) and aLGCIPL by 0.11%/year (95% confidence interval [CI] 0.07-0.19, p<0.001) corresponding to 26.4% (CI 13.1-44.2) and 27.2% (CI 14.3-43.1) of mean atrophy rates (aLpRNFL 0.42%/y [0.31-0.59], aLGCIPL 0.21%/y [0.15-0.29]).

Conclusions:

Carriers of the minor allele of rs10191329 seem more prone to MS-related tissue damage. While clinical implications are currently unclear, stratification for this genotype in clinical trials may be reasonable.