A Tiny Genetic Change That May Predict MS Treatment Success

Multiple sclerosis (MS) is a complex immune-mediated disease that affects millions worldwide. While we’ve made enormous strides in treatment over the past few decades, not every therapy works for every patient. And sometimes, the reasons why remain frustratingly mysterious.

One such case involves natalizumab (Tysabri®), a powerful second-line treatment for MS that works by preventing immune cells from entering the brain and spinal cord, thereby reducing inflammation and slowing disease progression. For many patients, natalizumab can be life-changing. But for a subset, it simply doesn’t deliver.

A study by Malak Al-Mojel and colleagues shines a spotlight on a potential genetic reason why — and it comes down to a single change in the DNA code of a gene called GP6.

The Study at a Glance
The researchers followed MS patients in Kuwait who were receiving natalizumab. They split participants into two groups:

Responders – those whose symptoms stabilized or improved, with no relapses or new lesions seen on MRI.

Non-responders – those who continued to worsen, relapsed, or developed new brain lesions despite treatment.

In the initial exome sequencing (a type of genetic analysis focusing on the protein-coding regions of DNA) of 33 patients, the team found one genetic difference that stood out:

A missense variant in the GP6 gene, specifically rs2304166 (c.940C>G; p.P314A).

When they tested a larger group of 86 patients, the results held up:

Those with two copies of the “C” variant (CC genotype) were far more likely to respond poorly to natalizumab.

The odds ratio? 22.18 — meaning CC patients were over 22 times more likely to be non-responsive compared to those without this genetic makeup.

What’s GP6 and Why Might It Matter?
The GP6 gene encodes glycoprotein VI, a receptor found on platelets (the blood cells that help with clotting). Its main job is to bind to collagen at injury sites, triggering platelet activation and clot formation. This helps maintain the integrity of blood vessels during inflammation.

Here’s where it gets interesting:

The rs2304166 variant changes one amino acid in GP6 — from proline to alanine at position 314.

This seemingly small swap happens in a highly conserved region of the protein, possibly altering its structure or stability.

The researchers hypothesize that this alteration could make GP6 less stable on platelet surfaces, impacting how well blood vessels repair themselves during inflammation. In the brain, that might mean more microvascular damage and poorer neurological outcomes — potentially counteracting natalizumab’s benefits.

Not Just About Relapses
Interestingly, most CC genotype non-responders didn’t show new lesions on MRI. Instead, they experienced progressive disability as measured by the Expanded Disability Status Scale (EDSS). This suggests the genetic effect might not be about immune cells sneaking into the brain (which natalizumab blocks) but rather about subtle vascular or neurodegenerative processes that the drug doesn’t address.

The study also points to possible links with thrombocytopenia (low platelet count), a rare but known side effect of natalizumab. If someone’s platelets are already functionally impaired due to GP6 changes, the drug’s impact on platelet biology could further tip the balance toward poor outcomes.

Why This Matters
If confirmed in larger and more diverse populations, GP6 rs2304166 could serve as a pharmacogenetic biomarker — a genetic clue to help doctors predict whether natalizumab will work for a given patient. That would be a big step toward personalized medicine in MS care.

Instead of a one-size-fits-all approach, neurologists could screen patients for this variant and consider alternative treatments early on for those at high risk of non-response.

The Road Ahead
The findings are compelling but not definitive. Key next steps include:

Replication studies in larger, ethnically varied cohorts.

Functional studies to see exactly how the variant changes GP6’s structure and function.

Exploring whether combining natalizumab with therapies that support vascular health could help CC genotype patients.

For now, the work of Al-Mojel et al. adds another layer to our understanding of MS treatment variability — and reminds us that even a single DNA letter change can ripple through biology in profound ways.

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:
Al-Mojel, M., Alroughani, R., Kannankeril, T. et al. GP6 rs2304166 polymorphism is associated with response to natalizumab in multiple sclerosis patients. Mult Scler Demyelinating Disord 4, 2 (2019). https://doi.org/10.1186/s40893-019-0039-0