Genes, Iron, and the Mind: How Subtle DNA Variations Shape the Severity of Multiple Sclerosis
Multiple sclerosis (MS) remains one of the most enigmatic neurological diseases—its causes are multifactorial, its progression unpredictable. While we know that MS is an autoimmune, inflammatory, and neurodegenerative disorder affecting the central nervous system, scientists are still working to understand why some patients experience mild, relapsing disease, while others face relentless progression and disability.
In a new 2025 study published in the International Journal of Molecular Sciences, Tamara Djuric and colleagues from the University of Belgrade tackled this question from a genetic angle. Their research sheds light on how functional variants in specific genes—particularly those tied to ferroptosis (iron-dependent cell death)—might influence disease severity and neurodegeneration in MS.
A Genetic Focus: From Immunity to Ferroptosis
For years, MS research centered on immune-related genes, especially those within the HLA (human leukocyte antigen) complex. The HLA-DRB115:01* allele remains the strongest known genetic risk factor for developing MS. But the story doesn’t end there.
Recent evidence suggests that processes like oxidative stress and ferroptosis—a regulated form of cell death triggered by iron and lipid peroxidation—also play key roles in MS progression. These pathways are especially relevant to neurodegeneration, which dominates the later stages of the disease.
Building on their earlier RNA sequencing work, Djuric’s team identified three ferroptosis-related genes that stood out in MS patients:
CDKN1A (p21) – involved in cell cycle regulation and T cell activation
EGLN2 – a key oxygen sensor linked to hypoxia responses
MAP1B – essential for axonal growth and stability
They then asked: Could genetic variants that regulate these genes influence how severe MS becomes?
Study Design: Decoding Genetic Signals in 845 Patients
The study analyzed seven gene variants in 845 Serbian MS patients, including:
604 with relapsing–remitting MS (RRMS)
241 with progressive MS (PMS) (both primary and secondary)
In addition to genotyping for HLA-DRB115:01, the researchers assessed neurological severity using standard measures:
EDSS (Expanded Disability Status Scale)
MSSS (Multiple Sclerosis Severity Score)
gARMSS (Age-Related Global MS Severity Score)
They also looked at mRNA expression, plasma lipid peroxidation, and iron metabolism markers—connecting genetics with molecular and clinical outcomes.
Key Findings: Sex-Specific and Functional Genetic Insights
1. MAP1B Variant and Female-Specific MS Progression
The MAP1B rs62363242 variant emerged as particularly significant:
Women carrying the rare A allele were more likely to develop progressive MS, independent of HLA-DRB115:01.
The same variant correlated with lower serum iron and higher transferrin levels—linking iron metabolism to neurodegeneration.
MAP1B plays a crucial role in axonal growth and myelination. Disruptions in its regulation could impair neuronal repair, potentially explaining the sex-specific vulnerability observed.
2. CDKN1A Haplotypes Influence Gene Expression and Disability
Two CDKN1A variants (rs3176326 and rs3176336) formed haplotypes that significantly affected CDKN1A mRNA levels in both RRMS and SPMS patients.
Patients carrying the GT haplotype showed:
Higher CDKN1A expression
Higher EDSS scores (greater disability)
Since CDKN1A (also known as p21) modulates T cell proliferation and microglial inflammation, its overexpression might exacerbate neuroinflammatory damage or impair remyelination.
3. EGLN2 Variant Tied to Disease Severity and Oxidative Stress
The EGLN2 rs111833532 variant correlated with worse neurological outcomes—higher EDSS, MSSS, and gARMSS scores—in RRMS patients.
Interestingly, carriers also showed elevated levels of 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation and ferroptosis.
EGLN2 acts as an oxygen sensor and regulator of hypoxia pathways. Its link to both hypoxia and oxidative stress strengthens the case for metabolic DYSFunction as a driver of MS progression.
4. DYSF–EGZNF638Variant and Male Disability Progression
For male patients, the DYSF–EGZNF638rs10191329 variant (previously identified by a GWAS) was associated with greater disability. This suggests sex-specific genetic pathways may shape disease trajectories differently in men and women—a theme increasingly recognized in MS research.
5. Lipid Peroxidation and HLA Susceptibility
The study also revealed that carriers of the HLA-DRB1*15:01 risk allele had higher serum levels of HEL, a biomarker of lipid peroxidation. This finding connects traditional immune susceptibility with oxidative stress—a potential bridge between inflammation and neurodegeneration.
The Bigger Picture: Toward Personalized MS Genetics
This study offers compelling evidence that ferroptosis-related pathways intersect with MS severity, expanding the field beyond immune-centric models. Key takeaways include:
Sex-specific genetics matter: Some variants influence disease progression differently in men and women.
Gene regulation is as crucial as coding mutations: Most significant variants were located in non-coding regions that control expression.
Ferroptosis links inflammation and neurodegeneration: Iron metabolism and lipid peroxidation could be therapeutic targets.
The authors emphasize that larger, multi-ethnic cohorts are needed to validate these findings. However, their integrative approach—combining genotyping, transcriptomics, and biochemical profiling—sets a strong example for multi-layered precision medicine research in MS.
Final Thoughts
As we move toward a more holistic view of multiple sclerosis, studies like this remind us that the brain’s iron balance, oxygen sensing, and cellular resilience are just as vital as immune regulation. By decoding these subtle genetic regulators, researchers are paving the way for more personalized therapies aimed not only at controlling inflammation but also at preserving neuronal integrity.
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:
Loginovic P., Wang F., Li J., Ferrat L., Mirshahi U.L., Rao H.S., et al. (2024). Applying a genetic risk score model to enhance prediction of future multiple sclerosis diagnosis at first presentation with optic neuritis. Nature Communications, 15, 1415. https://doi.org/10.1038/s41467-024-44917-9
