Unlocking MS Progression: Genetics and Biomarkers

A recent study in the Annals of Neurology sheds light on how a specific genetic variant, rs10191329, influences disability progression in multiple sclerosis (MS). The research team, led by Maria Protopapa and Frauke Zipp, investigated the impact of this genetic risk variant on neuroaxonal damage, measured by serum neurofilament light chain (sNfL) levels, and disability progression in people with MS (pwMS). Here's a breakdown of their findings and what it could mean for personalized medicine in MS.

Decoding the Genetics of MS Progression
While numerous genetic risk factors have been linked to MS susceptibility, the connection between genetics and disease progression remains less clear. This study homes in on the rs10191329 variant, located in the DYSF-ZNF638 locus, which encodes dysferlin. Previous research indicated that homozygous carriers of the risk allele (rs10191329AA) might experience a quicker time to needing a walking aid and display increased brainstem and cortical pathology.

However, some studies have contested these findings, highlighting the need for further investigation. The researchers aimed to explore whether disability accrual in homozygous (rs10191329AA) patients is preceded by increased sNfL levels, a marker of neuroaxonal damage.

Study Design and Methods
The study involved a cohort of 740 pwMS, with a mix of prospective (n = 658) and retrospective (n = 82) monitoring. The prospective group was followed every 2 years for less than a decade, while the retrospective group had data collected for up to 40 years. Researchers assessed clinical outcomes using the Expanded Disability Status Scale (EDSS), disability accrual, and progression to secondary progressive MS (SPMS). They also measured sNfL levels using single-molecule array. Statistical analyses included Kaplan–Meier and Cox proportional hazards analyses, as well as generalized mixed-effect models.

Key Findings
* Early sNfL Elevation: At the time of MS diagnosis, there were no significant differences in sNfL levels among different rs10191329 variant carriers. However, about 4 years post-diagnosis, homozygous carriers (rs10191329AA) showed significantly higher sNfL levels compared to non-carriers and heterozygous carriers.

* Increased Disability: Homozygous carriers exhibited a steeper increase in disability measures and a higher probability of developing SPMS.
* Long-Term Disability: In the retrospective cohort, the homozygous (rs10191329AA) group had significantly higher EDSS scores at 5 to 10 years and beyond 10 years after diagnosis, compared to non-carriers.
* Genetic Impact on Disability Accrual: The study found a significant impact of the rs10191329 allele dosage on disability accrual over time, with homozygous carriers accumulating disability faster.
* SPMS Conversion: Homozygous carriers had a higher risk of reaching an EDSS score of ≥4.5 and transitioning to SPMS.
* Predictive Power of rs10191329AA: The rs10191329AA variant was identified as a significant predictor of reaching EDSS hallmarks and SPMS conversion.

Implications for Personalized Medicine
These findings suggest that the rs10191329 genetic variant could serve as a biomarker for disease progression in MS. By identifying individuals at higher risk early on, clinicians can potentially tailor treatment strategies to slow down disability accrual and delay SPMS development.

Potential Conflicts
The authors declare no relevant conflicts of interest.

Limitations
The authors note some limitations to the study:
* Relatively small size of the retrospective cohort.
* Lack of disability confirmation.

Future Directions
The authors suggest several avenues for further research:

* Large, multicenter studies to validate these findings.

* Studies to estimate the potential impact of treatment on disability accrual, using clinical trial data.

By combining the MS severity risk genotype with the sNfL biomarker, future research could refine risk assessment and enable more personalized treatment approaches in MS.

Disclaimer: This blog post is based on the provided research article and is intended for informational purposes only. It is not intended to provide medical advice. Please consult with a healthcare professional for any health concerns.

References:
Protopapa, M., Steffen, F., Schraad, M., Ruck, T., Öztürk, M., Hanuscheck, N., ... & Zipp, F. (2024). Increased Disability Progression in rs10191329AA Carriers with Multiple Sclerosis Is Preceded by Neurofilament Light Chain Elevations. Annals of Neurology.