How Tiny Genetic Variations May Tip the Scales Toward Multiple Sclerosis: The Hidden Role of Oxidative Stress

Multiple sclerosis (MS) remains one of the most mysterious neurodegenerative diseases. It is an autoimmune condition where the body’s immune system attacks the protective covering (myelin) of nerve fibers in the brain and spinal cord. This leads to disrupted nerve signaling, progressive disability, and a wide range of symptoms — from fatigue and vision problems to paralysis.

Despite decades of research, the precise cause of MS is still unclear. Scientists agree it arises from a complex interplay between genetic and environmental factors — such as infections, smoking, vitamin D deficiency, and obesity. But in recent years, attention has shifted toward oxidative and nitrative stress — damaging cellular processes that may play a crucial role in triggering and worsening MS.

A 2022 study by researchers from the University of Łódź, Poland, takes a closer look at this connection. Published in Scientific Reports, their work explores how subtle genetic variations in key oxidative stress–related genes might influence MS risk.

Oxidative and Nitrative Stress: A Hidden Driver in MS
Our cells constantly deal with reactive molecules like reactive oxygen species (ROS) and reactive nitrogen species (RNS). Under normal conditions, antioxidant enzymes neutralize these molecules to prevent damage. However, when ROS and RNS levels overwhelm antioxidant defenses — a state called oxidative stress — cellular structures like DNA, lipids, and proteins can be harmed.

In the brain, which consumes large amounts of oxygen and has relatively weak antioxidant defenses, oxidative stress can be particularly destructive. It damages neurons and myelin, promotes inflammation, and may accelerate MS progression.

The key enzymes involved in maintaining redox balance include:

Nitric oxide synthases (NOS1, NOS2) – produce nitric oxide, which can act as both a signaling molecule and, in excess, a source of RNS.

Superoxide dismutase 2 (SOD2) – converts superoxide radicals into hydrogen peroxide.

CATalase (CAT) and glutathione peroxidase 4 (GPX4) – further detoxify hydrogen peroxide and lipid peroxides.

Given their critical roles, genetic variations in these enzymes could shift the oxidative balance — possibly predisposing individuals to diseases like MS.

The Study: Genetic Variants Under the Microscope
The Polish team investigated five single-nucleotide polymorphisms (SNPs) — small DNA sequence changes — in 142 MS patients and 140 healthy controls. The SNPs examined were:

NOS1 (rs1879417) NOS2 (rs2297518) SOD2 (rs4880) CAT (rs7943316) GPX4 (rs713041) Using TaqMan® genotyping assays, the researchers determined each participant’s genotype and statistically assessed whether specific genetic variants were linked to a higher or lower MS risk.

What They Found: Genetic Patterns Linked to MS Risk
NOS2 (rs2297518) – A Strong Connection
This gene stood out. Individuals with the C/C genotype or C allele had a significantly higher risk of developing MS, while those carrying the T allele seemed protected. NOS2 encodes inducible nitric oxide synthase (iNOS), which can produce large amounts of nitric oxide under inflammatory conditions — potentially contributing to neural damage.

SOD2 (rs4880) – A Protective Effect
The C/C genotype (and C allele) of SOD2 was associated with a reduced MS risk, while the T allele increased susceptibility. SOD2 helps detoxify superoxide radicals in mitochondria — its reduced function could exacerbate oxidative stress and neuronal injury.

CAT (rs7943316) – Increased Risk in Heterozygotes
Unexpectedly, individuals with the A/T genotype of CATalase showed an increased MS risk. Since CATalase detoxifies hydrogen peroxide, changes in its activity could influence redox homeostasis.

GPX4 (rs713041) – Dual Roles
The C/C genotype and C allele were linked with a lower risk, whereas the T/T genotype and T allele increased susceptibility. GPX4 is vital for preventing lipid peroxidation — its impairment can worsen neuronal oxidative damage.

NOS1 (rs1879417) – No Significant Link
Unlike NOS2, this gene’s variant didn’t show a clear association with MS in this population.

Genetic Interactions: The Risk Is in the Combinations
The researchers also looked beyond single genes. Some combinations of SNPs across different genes amplified or reduced MS risk:

NOS2 + SOD2 (T/C–C/C) combined genotype → higher MS risk.

NOS2 + GPX4 (T/T–C/C) → increased risk, while T/C–T/T reduced it.

NOS1 + NOS2 gene pair showed a protective synergistic interaction, suggesting complex regulatory effects between nitric oxide pathways.

Interestingly, gender-specific patterns also emerged.

For example, NOS2 risk variants affected both men and women, but SOD2 and GPX4 polymorphisms were more influential in women and men, respectively.

What Does This Mean for MS Research?
This study provides preliminary — but valuable — evidence that genetic variations in oxidative and nitrative stress-related genes can influence MS susceptibility. These findings add to a growing body of evidence linking redox imbalance to neurodegenerative and autoimmune diseases.

Importantly, the results highlight that oxidative stress is not just a byproduct of MS — it may be part of its root cause. Identifying genetic markers that predispose individuals to higher oxidative stress could open doors for:

Personalized risk assessment

Preventive strategies

Targeted antioxidant therapies

However, the authors caution that their study involved a relatively small cohort and focused on a single population. Larger, multi-ethnic studies are needed to confirm these associations and understand the underlying molecular mechanisms.

The Takeaway
Multiple sclerosis is not caused by a single factor, but rather a network of genetic and environmental influences. This research underscores the importance of our oxidative defense system in maintaining neurological health — and how subtle genetic differences in enzymes like NOS2, SOD2, CAT, and GPX4 might tip the balance toward disease.

As we move closer to unraveling MS’s genetic complexity, one thing becomes clear: managing oxidative stress — through lifestyle, diet, or therapeutics — could be a key part of the puzzle in slowing or preventing disease progression.

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:
Wigner, P., Dziedzic, A., Synowiec, E. et al. Variation of genes encoding nitric oxide synthases and antioxidant enzymes as potential risks of multiple sclerosis development: a preliminary study. Sci Rep 12, 10603 (2022). https://doi.org/10.1038/s41598-022-14795-6