Decoding Multiple Sclerosis: How Genetics Could Predict Disease Severity and Treatment Response

Multiple sclerosis (MS) is one of the most challenging neurological diseases to treat. This chronic autoimmune condition disrupts communication between the brain and body by attacking the protective myelin sheath around nerve fibers. The result is a wide range of symptoms—from fatigue and vision problems to severe mobility issues—that can dramatically reduce quality of life. Despite decades of research, there is still no cure, and existing treatments often come with harsh side effects or inconsistent effectiveness.

A recent study published in Scientific Reports (2025) takes an exciting step forward. The research team combined cutting-edge genetic and proteomic techniques to pinpoint potential therapeutic targets for MS, offering a roadmap for developing safer, more precise treatments.

Why New Approaches Are Needed in MS Research
Current therapies—such as immunomodulatory drugs, corticosteroids, and monoclonal antibodies—help manage MS but come with significant drawbacks. Patients may experience increased infection risks, organ toxicity, or variable responses depending on their genetic background and disease subtype. To overcome these hurdles, scientists are now turning to multi-omics approaches, which integrate information across genetics, proteomics, and molecular biology to reveal the root causes of disease.

The Power of Mendelian Randomization
The study’s backbone is Mendelian randomization (MR)—a statistical method that uses genetic variants as “natural experiments” to test whether certain proteins or biomarkers are causally linked to a disease. Think of it as using nature’s own randomized trial design, but at the DNA level.

By analyzing two large plasma protein datasets (from Iceland and the UK Biobank), the researchers identified dozens of proteins potentially involved in MS. Then, they validated these findings with Bayesian colocalization analysis, a method that checks whether the same genetic variant drives both protein levels and disease risk.

Key Discoveries: Three Genetic Targets
From this rigorous multi-step process, three standout genes emerged as promising drug targets:

EVI5 (Ecotropic Viral Integration Site 5)

Plays a role in cell cycle regulation and T-cell differentiation.

Variants in EVI5 disrupt immune balance, potentially fueling MS.

Encouragingly, it also influences myelin repair, suggesting dual benefits in controlling inflammation and promoting regeneration.

OGA (O-GlcNAcase)

Regulates protein glycosylation, a key modification affecting cell signaling, metabolism, and immune function.

Imbalances in OGA activity may destabilize myelin proteins and worsen autoimmune attacks.

Inhibitors of OGA are already under investigation and may have therapeutic potential in MS.

TNFRSF14 (also known as HVEM)

A receptor that orchestrates immune cell communication.

Dysregulation leads to overactive immune responses against the central nervous system.

Its dual role—stimulating and inhibiting immune pathways—makes it a particularly intriguing therapeutic target.

Beyond Genes: Pathways and Drugs
The researchers didn’t stop at gene discovery. They mapped how these genes interact with others through protein–protein networks and enriched pathways such as NF-κB signaling and cytokine–cytokine receptor interactions—both central to inflammation in MS.

From there, they predicted potential drug candidates. Notably:

Simvastatin (a cholesterol-lowering drug)

Luteolin (a natural flavonoid with anti-inflammatory properties)

DL-mevalonic acid (a metabolic compound)

Molecular docking simulations confirmed that these compounds can bind effectively to MS-related proteins, strengthening the case for repurposing them as treatments.

Why This Matters
This study is more than an academic exercise—it provides a scientific blueprint for next-generation MS therapies. By linking genetic variants, plasma proteins, and disease outcomes, the researchers have:

Identified EVI5, OGA, and TNFRSF14 as high-priority drug targets.

Highlighted existing compounds that might be repurposed for MS.

Opened the door to precision medicine, where treatment is tailored to an individual’s molecular profile.

Looking Ahead
The findings are promising, but the journey from discovery to treatment is long. The study was conducted primarily in European populations, raising questions about generalizability to other ethnic groups. Clinical validation—in both cell and animal models, followed by human trials—will be crucial.

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:
Yang, W., Liu, c., Li, Z. et al. Multi-omic biomarkers associated with multiple sclerosis: from Mendelian randomization to drug prediction. Sci Rep 15, 9421 (2025). https://doi.org/10.1038/s41598-025-94303-8