Code of Multiple Sclerosis: How Genetics and Epigenetics Reveal New Drug Possibilities
Multiple sclerosis (MS) is a chronic autoimmune disorder of the central nervous system (CNS) that affects more than two million people worldwide. Despite decades of research, the causes of MS remain only partially understood, and current treatments mainly focus on managing symptoms or slowing disease progression.
A study by researchers at the University of Texas Health Science Center at Houston has taken an integrative approach to this challenge. By combining genetic data, epigenetic modifications, and protein interaction networks, they uncovered novel insights into MS biology—and even identified existing drugs that could potentially be repurposed for treatment.
Why Genetics Alone Isn’t Enough
Large genome-wide association studies (GWAS) have identified over 230 genetic variants associated with MS. These variants explain about 48% of the heritability of the disease, highlighting the role of inherited risk. However, genetics is only part of the story.
Environmental factors also strongly influence MS risk, with Epstein–Barr virus (EBV) infection recently implicated as a major trigger. Epigenetics—the chemical modifications that regulate gene activity without changing the DNA sequence—provides a key link between genes and environment. For example, DNA methylation can turn genes on or off in response to external triggers.
But until now, how these genetic and epigenetic signals work together in MS has been unclear.
Building a Multi-Layered Network
The research team integrated three major data sources:
Genetic risk data from a massive MS GWAS (nearly 15,000 patients and 26,000 controls).
Epigenetic profiles from DNA methylation studies in immune cells from MS patients.
Human protein–protein interaction networks that map how gene products interact inside cells.
Using their in-house algorithm (dmGWAS v2.8), they created a gene regulatory network (GRN) enriched with both genetic and epigenetic signals.
This network contained 25 key genes with strong evidence of involvement in MS, including CD40, STAT3, and CIITA—genes central to immune system regulation. Interestingly, some genes were hypomethylated (more active) in MS, while others showed hypermethylation (less active), suggesting complex patterns of immune dysregulation.
Drug Discovery Through Network Biology
The team then asked: are any of these MS-associated genes already targeted by existing drugs?
The answer was yes. Their analysis revealed enrichment of druggable targets within the GRN. Notably, two genes are already targeted by approved MS therapies (HDAC1 by fingolimod and RELA by dimethyl fumarate).
Even more exciting, they identified repurposable drug candidates:
Vorinostat – a histone deacetylase (HDAC1) inhibitor with neuroprotective potential.
Sivelestat – a neutrophil elastase (ELANE) inhibitor studied for neuroinflammation.
Sorafenib – a tyrosine kinase inhibitor that reduces immune cell infiltration in MS models.
Acitretin – a STAT3 inhibitor currently used for psoriasis, another autoimmune condition.
Repurposing existing drugs could dramatically shorten the timeline to new MS treatments compared to developing drugs from scratch.
Insights Into MS Mechanisms
The network also provided fresh biological insights:
T follicular helper (TFH) cells—immune cells that help B cells mature—were the most enriched cell type, consistent with evidence of their role in MS-related neuroinflammation.
Viral pathways emerged as significant, reinforcing the suspected role of EBV in triggering MS.
A particularly striking finding involved the CD40 gene: certain MS-linked variants appear to reduce methylation in its promoter, boosting expression. Since CD40 also plays a role in EBV infection of B cells, this may be a molecular bridge between genetic risk and viral triggers.
Why This Matters
This study demonstrates the power of integrating multi-omics data—genetics, epigenetics, and systems biology—to better understand complex diseases. For MS, it not only sheds light on how genes and the environment interact, but also points to real-world therapeutic opportunities.
As the authors note, experimental validation will be essential before these drug candidates can move toward clinical use. But the approach itself—harmonizing genetic and epigenetic signals in a network framework—could be applied to other complex diseases, from Alzheimer’s to autoimmune disorders.
Takeaway
MS is a disease at the crossroads of genetics, environment, and immune dysfunction. By mapping how these forces converge at the molecular level, researchers are opening the door to smarter drug discovery. Instead of starting from scratch, we may already have powerful treatments hiding in plain sight.
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:
Manuel, A. M., Dai, Y., Jia, P., Freeman, L. A., & Zhao, Z. (2023). A gene regulatory network approach harmonizes genetic and epigenetic signals and reveals repurposable drug candidates for multiple sclerosis. Human molecular genetics, 32(6), 998-1009.
