Unlocking Personalized MS Treatment: How Your Genes Could Predict Response to Interferon-Beta

Multiple Sclerosis (MS) is a complex immune-mediated disease that primarily affects the central nervous system, leading to the demyelination of nerve axons and resulting in significant physical disability. It is a leading cause of disability among young adults, with higher prevalence in Europe, the USA, and Canada compared to regions like sub-Saharan Africa or East Asia. Women are also more commonly affected than men, typically between the ages of 20 and 40.

The most common form of MS, affecting over 80% of patients, is Relapsing-Remitting Multiple Sclerosis (RRMS). This type is characterized by periods of neurological dysfunction (relapses) followed by recovery, which may or may not leave residual deficits. While the exact causes of MS are not fully understood, it's believed to arise from a complex interplay of genetic and environmental factors.

For many years, Interferon-beta (IFNβ) has been a cornerstone first-line treatment for RRMS. There are several IFNβ products available, such as Betaferon, Avonex, and Rebif, which differ in their active ingredient forms (IFNβ-1a or IFNβ-1b) and administration methods. IFNβ works in a multifaceted way within the immune system: it reduces pro-inflammatory cytokines, increases anti-inflammatory cytokines, prevents immune cells from crossing the blood-brain barrier, inhibits T-cell activation, and promotes remyelination. Clinical trials have shown IFNβ to be effective in reducing patient disability, relapse frequency, and the appearance of new lesions.

The Challenge: Variable Response to IFNβ
Despite its proven benefits, a significant challenge in clinical practice is that many patients exhibit a suboptimal response to IFNβ, with 20% to 50% of individuals classified as non-responders, depending on the definition of treatment response used. This means that for a substantial portion of patients, this common treatment may not be as effective as hoped, often requiring lengthy clinical follow-up—up to two years—to determine its efficacy.

This is where the field of pharmacogenetics steps in. Pharmacogenetics studies how variations in an individual's DNA sequence influence their response to drugs. The ultimate goal is to move towards personalized medicine, where treatments are optimized for each patient based on their unique genetic makeup.

The Genetic Connection: Polymorphisms and IFNβ Response
The sources highlight that Single Nucleotide Polymorphisms (SNPs) – common genetic variations – in genes involved in MS disease progression, drug action (pharmacodynamics), metabolism, or IFNβ's mechanism of action can all impact the drug's effectiveness. Researchers have been actively investigating these genetic markers to predict who will respond well to IFNβ and who might need alternative therapies.

Review assessed the impact of these pharmacogenetic studies on IFNβ response in RRMS patients. The results suggest that detecting specific polymorphisms in several genes could potentially serve as future predictive markers for IFNβ treatment response in RRMS patients. However, it's crucial to note that many of these studies are still preliminary, often involving small sample sizes, which makes generalizing their findings difficult.

Let's dive into some of the genes and polymorphisms that have shown a promising link to IFNβ response:

Fragile Histidine Triad gene (FHIT): Located on chromosome 3, FHIT plays a role in modulating transcriptional activity and acts as an anti-oncoprotein by blocking the NF-kB pathway, which is critical for immune and pro-inflammatory responses. Deficient FHIT expression is considered a poor prognosis indicator in MS. A strong link was found between the C allele polymorphism rs760316 in the FHIT gene and better response to IFNβ treatment.

GTPase-activating protein and VPS9 domains 1 (GAPVD1): Found on chromosome 9, this gene is involved in regulating endocytosis and affects endosome morphology. Three polymorphisms in GAPVD1 showed a link with response: the T allele for rs10819043, the C allele for rs10760397, and the C allele for rs2291858.

Zinc Finger Protein 697 (ZNF697): Located on chromosome 1, its exact function is unknown, but zinc finger proteins are involved in diverse cellular processes like DNA recognition and transcriptional activity.

The A allele for ZNF697 polymorphism rs10494227 showed a strong link to IFNβ response. These three genes (FHIT, GAPVD1, ZNF697) were identified in a genome-wide association study (GWAS) that spanned multiple patient cohorts.

Other genes where specific polymorphisms have shown a link to IFNβ response include:

Gamma-aminobutyric acid receptor beta-3 (GABRB3): Located on chromosome 15, this gene encodes a receptor for the main inhibitory neurotransmitter in the central nervous system.

The A allele of polymorphism rs832032 was linked to a better response to IFNβ.

Glypican 5 (GPC5): Found on chromosome 13, this gene encodes a proteoglycan that influences IFNβ's binding to its receptor.

Patients with rs10492503-AA and rs1411751-CC genotypes responded better to treatment. However, another study on a larger cohort found no significant association for rs10492503.

Interferon Regulatory Factor 5 (IRF5): This gene on chromosome 7 plays a crucial role in regulating the IFN type I signaling pathway.

Patients with genotypes rs2004640-TT or rs4728142-AA had relatively poor responses to IFNβ.

Lymphocyte Function-Associated Antigen (LFA3 / CD58): Located on chromosome 1, this gene encodes a cell adhesion protein that promotes binding between antigen-presenting cells and T cells, modulating autoimmune responses.

Patients with the A allele for polymorphism rs12044852 responded better to IFNβ.

Membrane Cofactor Protein (MCP / CD46): This gene on chromosome 1 encodes a complement control protein that protects host cells from immune attack and co-stimulates T cells to produce anti-inflammatory molecules. Altered CD46 function is observed in MS patients.

Homozygous TT patients for rs2724385 showed a better response to treatment.

Myxovirus Resistance protein A (MxA): Encoded on chromosome 23, MxA is induced by IFNβ and prevents viral replication. MxA mRNA levels are considered a biomarker for IFNβ treatment efficacy.

A strong association was found between the genotype rs464138-AA and response to treatment.

Pellino 3 (PELI3): This ubiquitin ligase protein, encoded on chromosome 11, is involved in immune signaling cascades.

The A allele for polymorphism rs2277302 was linked to IFNβ response.

Conversely, some genes and their polymorphisms, despite being studied, did not show a significant link to clinical outcomes in RRMS patients treated with IFNβ. These include NLRP3, USP18, IRF8, and IL28B. For instance, while IL28B is associated with IFNα response in hepatitis C, it showed no significant link to IFNβ response in MS. Similarly, USP18, a negative regulator of the IFN type I receptor pathway, was studied for its potential impact on IFNβ response, but the findings were not consistently significant.

The Road Ahead: More Research is Needed
While these findings are promising for the future of personalized medicine in MS, the sources emphasize several limitations in current research:

Small Sample Sizes: Many studies have been performed on relatively small groups of RRMS patients.

Lack of Uniformity: There is inconsistency in how "response to treatment" is defined across different studies.

Short Follow-up: The duration of patient follow-up in some studies may not be sufficient to fully generalize the results.

Complexity of Interactions: Most studies only analyze a few polymorphisms simultaneously and do not account for the potential cumulative effect of multiple SNPs in different genes.

Therefore, further research is urgently needed. This includes large-scale studies with longer-term follow-up and a uniform definition of treatment response to confirm these results. The primary goal is to identify reliable biomarkers that can predict how patients will respond to IFNβ therapy based on their genetic characteristics.

In conclusion, while we're not yet at the stage of routinely using genetic tests to guide IFNβ treatment for every MS patient, the research is steadily progressing. The detection of specific genetic polymorphisms holds significant promise as a future tool for personalized medicine in RRMS, helping healthcare professionals select the most beneficial treatment for each individual and avoid lengthy trial-and-error periods. This genetic insight offers a beacon of hope for optimizing care for those 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:
Martínez-Aguilar, L., Pérez-Ramírez, C., del Mar Maldonado-Montoro, M., Carrasco-Campos, M. I., Membrive-Jiménez, C., Martínez-Martínez, F., ... & Jiménez-Morales, A. (2020). Effect of genetic polymorphisms on therapeutic response in multiple sclerosis relapsing-remitting patients treated with interferon-beta. Mutation Research/Reviews in Mutation Research, 785, 108322.