A Genetic Brake on MS: How SLC9A9 Shapes Treatment Response
Multiple sclerosis (MS) remains one of the most challenging immune-mediated diseases to treat. While therapies like interferon beta (IFNβ) have been a cornerstone of treatment for relapsing-remitting MS (RRMS), not every patient benefits equally. Some stabilize, others continue to relapse, and predicting who will respond has been a persistent puzzle.
A 2015 study led by Federica Esposito, Filippo Martinelli Boneschi, Philip De Jager, and colleagues shines new light on this issue. Their work identifies a genetic clue—within a gene called SLC9A9—that may explain why some patients don’t respond to IFNβ.
Why Genetics Matter in MS Treatment
MS is notoriously variable: the same drug can be life-changing for one patient and ineffective for another. This heterogeneity points toward genetic and molecular differences that shape disease activity and drug response. If we can uncover genetic markers that predict treatment outcomes, doctors could tailor therapies to each patient—a step toward true personalized medicine.
The Discovery: A Genetic Variant Linked to Non-Response
The team conducted a genome-wide association study (GWAS) in MS patients treated with IFNβ. Out of over half a million genetic markers, one stood out: rs9828519, an intronic variant in the SLC9A9 gene.
Patients carrying the G allele of this variant were significantly more likely to relapse despite IFNβ treatment.
In fact, all patients with the GG genotype were non-responders.
This strong association was replicated in three independent cohorts from Italy, the U.S., and France, reinforcing the finding.
What is SLC9A9?
SLC9A9 encodes a sodium/hydrogen exchanger located in endosomes, small compartments within cells that regulate pH and help process signals. While not previously linked to MS, its function in immune cells made it a compelling candidate.
The study revealed:
SLC9A9 expression is boosted by IFNβ, both in vitro and in MS patients starting therapy.
But paradoxically, SLC9A9 expression is lower in patients with more active disease, suggesting it plays a protective role.
When researchers silenced SLC9A9 in T cells, these cells produced more interferon gamma (IFNγ)—a pro-inflammatory cytokine that drives MS pathology.
In other words, SLC9A9 may act as a brake on overactive immune responses. When its function is diminished (by genetics or expression changes), the immune system tilts toward inflammation.
Beyond IFNβ: A Broader Role in MS Disease Activity?
Interestingly, the variant in SLC9A9 was not strongly associated with response to glatiramer acetate (another first-line MS therapy). However, reduced SLC9A9 expression correlated with higher relapse risk regardless of treatment, suggesting that its role may extend beyond IFNβ response and into MS disease activity overall.
Why This Matters
This study is significant for several reasons:
Personalized Medicine – Identifying variants like rs9828519 could help predict which patients will respond to IFNβ, sparing others the time and side effects of ineffective therapy.
New Therapeutic Targets – Since SLC9A9 regulates T cell activation, it could be explored as a drug target in MS and potentially other autoimmune diseases like Crohn’s disease or rheumatoid arthritis.
Mechanistic Insights – By linking ion exchange, endosomal pH, and immune cell signaling, the study highlights a previously underappreciated pathway in MS.
Looking Ahead
While rs9828519 alone isn’t enough to dictate treatment decisions, it adds a critical piece to the puzzle. Future studies combining genetic, molecular, and clinical biomarkers could create predictive models of treatment response.
As the authors note, SLC9A9’s role in controlling T cell fate is especially intriguing. Modulating its activity—or the downstream effects on IFNγ—might open entirely new strategies for calming the overactive immune system in MS.
Take-Home Message
This pharmacogenetic study identifies SLC9A9 as a key regulator of MS disease activity and response to IFNβ therapy. By uncovering how a single genetic variant can shape treatment outcomes, it moves us closer to a future where MS care is not “one-size-fits-all,” but precisely tailored to each patient’s biology.
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:
Esposito, F., Sorosina, M., Ottoboni, L., Lim, E. T., Replogle, J. M., Raj, T., ... & De Jager, P. L. (2015). A pharmacogenetic study implicates SLC9a9 in multiple sclerosis disease activity. Annals of neurology, 78(1), 115-127.
