How Tiny Genetic Switches May Shape Multiple Sclerosis
Multiple sclerosis (MS) remains one of the most enigmatic immune-mediated diseases. Affecting around 2.8 million people globally, MS is characterized by the immune system attacking the central nervous system, leading to inflammation, demyelination, and progressive neurodegeneration. While environmental factors (like viral infections and vitamin D deficiency) are known contributors, the genetic underpinnings of MS are becoming increasingly clear.
A new study published in Heliyon (Stefanović et al., 2024) explores how subtle differences in gene expression—particularly in the ORMDL3 and GSDMB genes—interact with a known genetic risk variant in the IKZF3 gene (rs12946510) to influence the course of relapsing-remitting MS (RRMS).
The Genetic Region Under the Microscope: 17q12-21
Chromosome 17q12-21 has emerged as a genetic hotspot in autoimmune and inflammatory diseases. Within this locus sit several immune-related genes, including:
IKZF3: Encodes Aiolos, a transcription factor critical for T and B cell regulation.
ORMDL3: Involved in calcium signaling and sphingolipid metabolism, both essential for T cell activation and migration.
GSDMB: Recently discovered to play a role in pyroptosis (a form of inflammatory cell death), triggered by natural killer (NK) cells and cytotoxic T lymphocytes.
Previous genome-wide association studies (GWAS) identified the SNP rs12946510 in IKZF3 as a top-ranked MS risk variant. Importantly, this SNP acts as an expression quantitative trait locus (eQTL)—a regulatory variant that alters the activity of neighboring genes like ORMDL3 and GSDMB.
The Study Design: Patients, Controls, and Gene Expression
The research team analyzed 67 RRMS patients (15 in relapse, 52 in remission) and 50 healthy controls. Blood samples were collected, and the researchers measured gene expression levels of ORMDL3, GSDMB, and IKZF3 in peripheral blood mononuclear cells (PBMCs). They also genotyped each individual for rs12946510.
Key clinical parameters such as disability (EDSS), disease severity (MSSS), relapse rate, therapy status (interferon β treatment), and sex were factored into the analysis.
Key Findings
Lower ORMDL3 and GSDMB in MS patients
Both genes showed significantly reduced expression in RRMS patients compared to healthy controls. This suggests that reduced activity of these immune-regulatory genes could contribute to disease pathology.
Genetic influence of rs12946510
Patients carrying the rare TT genotype of rs12946510 had the lowest expression of ORMDL3 and GSDMB. This confirms the SNP’s role as an eQTL in MS. Interestingly, IKZF3 expression itself was not significantly altered by genotype.
Clinical correlations
ORMDL3 and GSDMB expression strongly correlated with each other.
IKZF3 expression correlated with MS disability scores (EDSS).
GSDMB levels were negatively associated with age of onset and current patient age.
GSDMB was higher during relapse than remission, suggesting a role in the inflammatory bursts of RRMS.
Therapy effects
Patients receiving interferon β therapy had higher GSDMB expression, and this effect interacted with rs12946510 genotype. This finding hints at a possible pharmacogenomic angle—how genetics and treatment intersect in shaping immune responses.
Why Do These Findings Matter?
This study strengthens the idea that non-coding genetic variants can influence autoimmune disease risk by regulating gene expression rather than altering protein structure directly.
ORMDL3 downregulation may unleash excessive T cell activation and enhance inflammation.
GSDMB downregulation may blunt immune cell–mediated pyroptosis, disrupting immune clearance mechanisms.
The interplay with rs12946510 highlights how a single SNP can ripple across multiple genes, tuning the immune system’s inflammatory balance.
Crucially, these findings provide a biological explanation for why some patients experience more severe or earlier disease progression, and why therapies like interferon β may have variable effects.
Looking Ahead
While the study is limited by its sample size, it provides a compelling framework for future research. Larger studies could validate these associations and explore therapeutic implications. Could rs12946510 or ORMDL3/GSDMB expression levels serve as biomarkers for MS severity or treatment response? Might targeted therapies restore balance in these pathways?
For now, this work underscores the importance of moving beyond “which genes are linked to MS” toward understanding how genetic variants functionally shape immune behavior.
Final Takeaway
The study by Stefanović and colleagues elegantly ties together genetics, gene regulation, and clinical outcomes in MS. By focusing on ORMDL3, GSDMB, and the IKZF3 rs12946510 variant, it illuminates a small but significant piece of the complex MS puzzle—bringing us closer to personalized approaches in managing this challenging disease.
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:
Stefanović, M., Stojković, L., Životić, I., Dinčić, E., Stanković, A., & Živković, M. (2024). Expression levels of GSDMB and ORMDL3 are associated with relapsing-remitting multiple sclerosis and IKZF3 rs12946510 variant. Heliyon, 10(3).
