When Genes Misfire: How Our DNA Shapes Multiple Sclerosis and Neuromyelitis Optica

Our brains are remarkable conductors, orchestrating the electrical symphony that powers everything from thought to movement. But what happens when the “insulation” around our brain’s wiring starts to fray? This is the devastating reality for millions living with multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD)—two major inflammatory demyelinating diseases of the central nervous system (CNS).

A 2023 review by Ortiz and colleagues in Genes (DOI: 10.3390/genes14071319) delves deep into the genetic architecture that underlies these diseases, offering insights into how genes and the environment shape their onset and progression. Let’s unpack their findings in plain language—without losing the scientific depth.

What Are Demyelinating Diseases?
Demyelinating diseases damage myelin, the fatty sheath that wraps around nerve fibers to speed up electrical communication between brain and body. When this sheath deteriorates, signals slow or stop—causing symptoms ranging from fatigue and muscle weakness to vision loss and paralysis.

While there are several demyelinating disorders, MS and NMOSD are the most prominent and complex, often misdiagnosed as one another due to overlapping symptoms. The key difference? In NMOSD, the immune system targets aquaporin-4 (AQP4)—a water channel protein found on astrocytes—whereas in MS, the attack is directed against myelin itself.

The Genetic and Environmental Puzzle of MS
1. A Disease of Geography and Genes
MS doesn’t strike evenly across the globe. It’s most common in northern Europe, North America, and other temperate regions, while it’s rarer near the equator. This “latitude gradient” hints at environmental influences—particularly sunlight exposure and vitamin D levels.

Vitamin D not only supports bone health but also modulates the immune system. Low levels can tilt immune balance toward inflammation, which may help explain why MS risk rises in areas with less sunlight.

2. The Viral Connection
Among infectious suspects, Epstein–Barr virus (EBV) stands out. Nearly every MS patient has been infected with EBV, suggesting it might “train” the immune system in harmful ways—triggering autoimmunity years later.

3. Family and Ethnic Patterns
MS runs in families: the risk for a sibling of an MS patient is roughly 30 times higher than average. However, identical twins—who share 100% of their DNA—are not always both affected, indicating that environment and epigenetics also play critical roles.

Inside the DNA: The Genetic Story of MS
Genetic research has transformed our understanding of MS. Early studies pointed to the human leukocyte antigen (HLA) region—particularly the HLA-DRB1*15:01 allele—as the strongest genetic risk factor. This gene helps immune cells recognize “self” from “non-self,” and certain variants make this recognition go awry.

But MS isn’t caused by a single gene. Genome-wide association studies (GWAS) have uncovered more than 200 risk loci—many involved in immune regulation. Notably:

IL7RA and IL2RA, which code for receptors on immune cells, influence how T cells grow and communicate.

TNFRSF1A, whose variant leads to overproduction of a soluble receptor that disrupts TNF signaling—mirroring the effects of some MS-worsening drugs.

VAV1, tied to immune signaling, inflammation, and disease severity.

Together, these variants explain about 25–30% of MS heritability, leaving a portion of “missing heritability” likely hidden in rare variants, epigenetic changes, or gene–environment interactions.

How Genes and Environment Interact
Genes don’t act alone. The study highlights fascinating gene–environment (GxE) interactions:

The HLA-DRB1*15:01 allele includes a vitamin D–responsive element in its promoter region—suggesting sunlight exposure can directly influence how this risk gene is expressed.

This provides a tangible biological link between sunlight, vitamin D levels, and genetic susceptibility.

Moreover, epigenetic modifications—chemical tags that turn genes “on” or “off” without changing the DNA sequence—can shape immune behavior. These may explain why identical twins with the same DNA often have different disease outcomes.

NMOSD: A Different Genetic Blueprint
Although NMOSD shares some features with MS, it is genetically and immunologically distinct. Most NMOSD patients produce AQP4 antibodies, and their genetic risk factors vary across ethnicities.

Key findings include:

HLA associations differ by population—DRB1*16:02 in Japanese and Chinese patients, DQB1*04:02 in Europeans, and DRB1*03:01 in Brazilians and Mexicans.

Non-HLA genes like IL-17, IL-7R, and PD-1 may contribute to immune dysregulation.

A variant in the TNXB gene (rs1150757) increases NMOSD risk up to 4.6-fold, especially in Latin American populations.

Interestingly, NMOSD is more common among women (up to 80%) and has higher prevalence in non-European populations, including Latin Americans and East Asians—suggesting complex interactions between ancestry and immune genetics.

Why These Findings Matter
Understanding the genetic basis of MS and NMOSD isn’t just academic—it’s paving the way for personalized medicine:

Predictive genetics could help identify at-risk individuals before symptoms appear.

Targeted therapies might correct specific immune signaling pathways.

Vitamin D supplementation or EBV vaccines may one day reduce disease incidence.

Moreover, knowing how MS and NMOSD differ at the molecular level prevents misdiagnosis and guides the use of appropriate treatments—since certain MS drugs can worsen NMOSD.

The Road Ahead
Ortiz et al.’s review underscores a key message: autoimmune diseases are not random errors—they are complex, genetically encoded miscommunications within our immune system.

Future research combining genomics, transcriptomics, and epigenomics will help decode these miscommunications and uncover why certain individuals, environments, and ethnicities intersect to ignite diseases like MS and NMOSD.

By piecing together these genetic clues, we’re moving closer to a world where neurological diseases are not just treated—but anticipated, personalized, and ultimately prevented.

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:
Ortiz GG, Torres-Mendoza BMG, Ramírez-Jirano J, et al. Genetic Basis of Inflammatory Demyelinating Diseases of the Central Nervous System: Multiple Sclerosis and Neuromyelitis Optica Spectrum. Genes. 2023;14(7):1319. https://doi.org/10.3390/genes14071319