Unveiling the Genetic Key to Multiple Sclerosis Treatment: The Role of ADAR in Predicting Interferon Beta Therapy Response

Multiple sclerosis (MS) is a complex immune-mediated neurodegenerative disease affecting the central nervous system (CNS), primarily impacting young adults. Despite the availability of various disease-modifying therapies, interferon-beta (IFN-β) remains one of the first-line treatments for MS, particularly for the relapsing-remitting form (RRMS). However, the response to IFN-β varies significantly among patients, with up to 50% not experiencing the desired therapeutic outcomes. Identifying reliable biomarkers that can predict an individual’s response to IFN-β before initiating treatment could prevent ineffective therapy and reduce unnecessary costs and delays in switching to more suitable alternatives.

Adenosine deaminase acting on RNA (ADAR), particularly the ADAR1 enzyme, plays a critical role in the IFN signaling pathway by editing double-stranded RNA (dsRNA) and modulating immune responses. Dysregulation of ADAR has been implicated in various autoimmune diseases, including MS. This study investigates the association between ADAR expression levels and single nucleotide variants (SNVs) in the ADAR gene, particularly rs2229857, with the response to IFN-β therapy in RRMS patients.

Study Design and Methods
The study involved 167 RRMS patients, categorized as responders (71 patients) or nonresponders (96 patients) based on their clinical outcomes following at least 12 months of IFN-β therapy. Clinical evaluations included the Expanded Disability Status Scale (EDSS), annualized relapse rate (ARR), and magnetic resonance imaging (MRI) findings. Patients were excluded if they had other neurological, psychological, or autoimmune disorders, or if they had a history of smoking, alcohol consumption, or chronic internal diseases that could affect drug metabolism.

Genomic DNA and RNA were extracted from blood samples collected before treatment initiation and after 15 months of therapy. High-resolution melting real-time PCR was employed to genotype the rs2229857 variant, and quantitative real-time PCR (qRT-PCR) was used to measure ADAR mRNA expression levels.

Results
The study found significant differences in ADAR expression and rs2229857 genotypes between responders and nonresponders. The allele A in rs2229857 was associated with a higher risk of nonresponse to IFN-β therapy. Nonresponders exhibited higher baseline ADAR mRNA levels than responders, suggesting that increased ADAR expression may be linked to resistance to IFN-β treatment.

Moreover, the study revealed that patients with the AA or GA genotypes of rs2229857 had a significantly lower likelihood of responding to IFN-β compared to those with the GG genotype. The odds ratios for nonresponse were 0.073 and 0.236 for the AA and GA genotypes, respectively, after adjusting for demographic and clinical factors.

Interestingly, responders showed a significant increase in ADAR expression after one year of therapy, while nonresponders did not exhibit substantial changes in ADAR levels. This lack of change in nonresponders could be due to an already saturated IFN-β-induced cascade, rendering it unresponsive to exogenous IFN-β.

Discussion
The findings of this study underscore the potential of ADAR expression levels and rs2229857 variants as predictive biomarkers for IFN-β therapy responsiveness in RRMS patients. The association between higher ADAR expression and the AA genotype with poor therapeutic outcomes suggests that ADAR plays a crucial role in modulating the IFN-β signaling pathway, which may impact the efficacy of the treatment.

These results align with previous research indicating that nonresponders to IFN-β therapy often exhibit higher baseline activity of IFN signaling pathways, making them less responsive to additional IFN-β stimulation. The differential expression of ADAR in responders versus nonresponders highlights the need for further studies to explore the mechanistic role of ADAR in MS and its potential as a target for therapeutic intervention.

Conclusion
This study provides compelling evidence that assessing ADAR expression levels and rs2229857 genotypes in RRMS patients could be a valuable strategy for predicting response to IFN-β therapy. Implementing such predictive biomarkers in clinical practice could help tailor treatment plans more effectively, improving patient outcomes and optimizing resource utilization. However, larger cohort studies and more refined experimental approaches are necessary to validate ADAR as a prognostic marker and fully understand its role in MS pathogenesis and treatment.

References:
Fakhr, F., Shaygannejad, V., Khorrami, M., Saberi, L., Mirmosayyeb, O., Sadeghi, E., & Kheirollahi, M. (2023). ADAR Expression and Single Nucleotide Variants in Multiple Sclerosis Patients Affect the Response to Interferon Beta Therapy. Global Medical Genetics, 10(03), 164-171.