GA Resistance in MS: Are Genetic Variations in HLA and IL-6 Involved?

Multiple sclerosis (MS) is a complex disease where the body's immune system mistakenly attacks the central nervous system, leading to inflammation and nerve damage. For many living with relapsing-remitting MS (RRMS), a common treatment is an immunomodulatory drug called glatiramer acetate (GA). Think of it as a way to dial down the immune system's overactivity. While GA can be very effective in preventing relapses and long-term disability for many, unfortunately, a significant number of individuals don't respond as well as hoped – a phenomenon known as GA resistance.

This lack of response is a puzzle that scientists are working hard to solve. If we could understand why some individuals don't benefit from GA, we could potentially develop more personalized and effective treatment strategies. That's precisely what a recent study published in Biochemical Genetics aimed to explore.

Peeking into Our Genes: The Focus on HLA and IL-6
This research team delved into the potential role of our genes, specifically looking at variations in the HLA-DRA, HLA-DQA1, and IL-6 genes. These genes are key players in our immune system. The HLA-DRA and HLA-DQA1 genes are involved in how our cells present antigens (foreign substances) to the immune system. The IL-6 gene provides instructions for making a protein (interleukin-6) that's involved in inflammation and the maturation of B cells, another type of immune cell. Given their central roles in immunity, these genes are naturally suspected to be linked to MS and potentially how people respond to immune-modulating drugs like GA.

The researchers focused on specific known variations (nucleotide variations) within these genes: rs3135388 and rs3135391 in HLA-DRA, rs9272346 in HLA-DQA1, and rs1800795 and rs1900796 in IL-6. They wanted to see if the presence of certain versions of these gene variations was more common in MS patients who didn't respond well to GA compared to those who did.

The Study: Comparing Responders and Non-Responders
The study involved 139 patients diagnosed with RRMS who had been treated with GA for at least a year. To accurately assess their response to the drug, the researchers looked at clinical relapses, changes in disability status using the Expanded Disability Status Scale (EDSS), and the appearance or growth of brain lesions on MRI scans taken at baseline and after 12 months of treatment. Based on these criteria, the patients were divided into two groups: responders (n=81) who showed benefit from GA, and non-responders (n=58) who did not.

The researchers then analyzed the DNA from the patients' blood to identify which versions of the targeted gene variations they carried using a technique called Real-Time Polymerase Chain Reaction (RT-PCR). They also collected data on potential environmental factors like vitamin D, B9 (folic acid), and B12 levels to see if these played a role.

What Did They Find?
Interestingly, when the researchers compared the distribution of the gene variations and their different forms (alleles) between the responder and non-responder groups, they found no significant differences. This suggests that, at least in this group of patients, the specific gene variations in HLA-DRA, HLA-DQA1, and IL-6 that they investigated were not significantly linked to whether a patient responded to GA or not.

Similarly, the study found no significant relationship between the measured vitamin levels and the different versions of the genes.

However, the study did reveal that at the beginning of the study (baseline), the non-responder group had significantly higher EDSS scores and a greater lesion load on their initial MRI scans compared to the responder group. This implies that patients with more established disability and more brain lesions at the start of GA treatment might be less likely to respond effectively. The study also noted that females were considerably more represented in both the responder and non-responder groups, which aligns with the general higher prevalence of MS in women.

Looking Ahead: The Promise of Personalized Medicine
While this study didn't find a direct link between the specific gene variations and GA resistance, the researchers emphasize that their sample size might have been too small to detect subtle effects. They suggest that future studies with a larger number of patients are needed to draw more definitive conclusions.

The authors highlight the importance of pharmacogenetic studies, which investigate how our genes influence our response to medications. By understanding the drug-gene relationships in MS patients treated with GA, we could potentially move towards personalized treatment strategies. Imagine a future where a patient's genetic profile could help doctors predict how likely they are to respond to GA, allowing them to choose the most appropriate treatment from the outset.

This study, while not providing immediate answers, underscores the ongoing effort to unravel the complexities of MS and drug response. By continuing to investigate the interplay between our genes and how we react to therapies, we can pave the way for more effective and tailored treatments for individuals living with multiple sclerosis.

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:
Sahbaz, A., Selcuk, B.O., Domac, F.M. et al. Effects of HLA-DRA, HLA-DQA1 and IL-6 Gene Variations to Glatiramer Acetate Resistance in Multiple Sclerosis Patients. Biochem Genet (2025).