Unraveling the Genetic Basis of MS Relapses: The Role of WNT9B Variation
Multiple Sclerosis (MS) is a chronic autoimmune disorder characterized by inflammation and neurodegeneration in the central nervous system. While significant progress has been made in identifying genetic factors contributing to MS susceptibility, understanding the genetic basis of disease heterogeneity, particularly relapse risk, remains challenging. Relapses in MS, defined as episodes of new or worsening neurological symptoms, are a major concern as they contribute to long-term disability. A recent study published in the Annals of Neurology by Vandebergh et al. (2021) sheds light on the genetic underpinnings of relapse hazard in MS, revealing a critical role for the WNT9B gene.
The primary objective of the study was to identify genetic variations associated with relapse hazard in MS by conducting a genome-wide association study (GWAS) on a large cohort of patients. The researchers aimed to understand how genetic factors influence the frequency and severity of relapses, thereby contributing to disease heterogeneity.
Discovery Phase
The study included 506 MS patients from the University Hospitals Leuven, diagnosed according to the 2017 McDonald criteria. Genetic data were obtained using the Illumina Global Screening Array, which included over 700,000 variants. A stringent quality control process was applied to ensure high-quality genetic data. Survival analysis, using Cox proportional hazards models, was employed to assess the time to relapse, capturing a total of 1,412 relapses before any immunomodulatory treatment was initiated.
Replication Phase
The replication phase involved an independent cohort of 485 MS patients from the Technical University of Munich. The same genotyping and quality control procedures were applied to ensure consistency. The replication cohort included 819 relapses over a median baseline duration of 0.5 years.
Key Findings
Identification of rs11871306 in WNT9B:
The low-frequency genetic variant rs11871306 within the WNT9B gene was identified as a significant predictor of relapse hazard. Carriers of the minor allele had more than double the relapse hazard compared to non-carriers (HR = 2.15, p = 2.07 × 10⁻¹⁰).
Gene ontology pathway analysis highlighted the “response to vitamin D” pathway as significantly associated with relapse hazard, suggesting a potential modulatory role of vitamin D in MS relapse risk.
The study underscores the importance of genetic factors in determining disease heterogeneity in MS. Unlike susceptibility variants, which primarily influence the risk of developing MS, the identified variants in WNT9B specifically affect relapse frequency. This distinction is crucial for developing targeted therapies aimed at reducing relapse rates and improving patient outcomes.
The WNT9B gene is part of the Wnt signaling pathway, which plays a pivotal role in various biological processes, including immune regulation and CNS homeostasis. The identified variant, rs11871306, disrupts a transcription factor binding site, potentially altering gene expression and contributing to increased relapse hazard.
The study also highlights the interplay between the Wnt signaling pathway and vitamin D response. Vitamin D is known to modulate immune responses, and its deficiency has been associated with increased MS relapse risk. The findings suggest that enhancing vitamin D levels might mitigate the impact of genetic variants in the Wnt pathway on relapse frequency.
Conclusion
Vandebergh et al. (2021) provide compelling evidence that genetic variation in WNT9B significantly influences relapse hazard in MS. The study's insights into the genetic basis of relapse risk pave the way for personalized therapeutic strategies targeting specific genetic pathways, ultimately aiming to reduce relapse rates and improve the quality of life for MS patients.
References
Vandebergh, M., Andlauer, T. F., Zhou, Y., Mallants, K., Held, F., Aly, L., ... & Goris, A. (2021). Genetic variation in WNT9B increases relapse hazard in multiple sclerosis. Annals of neurology, 89(5), 884-894.
