Exploring the Genetic Roots of Multiple Sclerosis: The Role of HHEX Polymorphism rs7923837

Multiple sclerosis (MS) is a complex, immune-mediated neurodegenerative disease characterized by chronic inflammation, demyelination. Despite advances in understanding its pathology, the exact genetic factors contributing to MS susceptibility remain elusive. Recent studies have shed light on various genetic risk factors, among which the HHEX (hematopoietically-expressed homeobox) gene has gained significant attention. The single nucleotide polymorphism (SNP) rs7923837, located near the HHEX gene, has been implicated in MS pathogenesis, as well as in other conditions like type 2 diabetes and altered lipid metabolism, suggesting a broader role in systemic diseases. This article delves into the impact of rs7923837 on HHEX expression and its potential implications in MS.

HHEX and Its Role in MS
HHEX is a versatile transcription factor involved in various cellular processes, including embryonic development, inflammation regulation, and metabolic control. In the context of MS, HHEX has been recognized for its role in modulating inflammatory responses in microglia, a type of glial cell in the central nervous system (CNS) that plays a crucial role in immune defense. The SNP rs7923837 has been identified as an expression quantitative trait locus (eQTL), meaning it influences the expression levels of the HHEX gene. Understanding this SNP's impact on HHEX expression in MS patients versus healthy controls can provide insights into its role in disease progression.

Lower HHEX Expression in MS Patients
The study under discussion reveals that MS patients exhibit significantly lower HHEX mRNA levels in peripheral blood mononuclear cells (PBMCs) compared to healthy controls. This finding aligns with previous reports indicating that rs7923837AA, the homozygous minor allele, is associated with reduced HHEX expression in healthy individuals. Interestingly, while this reduced expression is observed in both MS patients and controls carrying the rs7923837AA genotype, the differences did not reach statistical significance when comparing heterozygotes and major allele carriers. This suggests that while the SNP influences HHEX expression, other factors may contribute to the variability seen in MS patients.

Nuclear Localization of HHEX in MS
HHEX functions as a transcription factor, and its activity is closely linked to its subcellular localization. Confocal microscopy analysis in this study revealed that MS patients homozygous for the rs7923837*AA genotype exhibited increased nuclear localization of HHEX compared to controls. This shift in localization suggests that in MS, HHEX may be more actively involved in regulating gene expression related to immune responses, potentially contributing to the disease's pathology.

Metabolic Implications
Metabolic reprogramming is a hallmark of immune cell activation, and the study explored this aspect by analyzing the metabolic profiles of PBMCs from MS patients and healthy controls. Interestingly, MS patients with the rs7923837*AA genotype displayed a more energetic phenotype, characterized by higher glycolytic activity even in resting conditions. This pre-activation metabolic state could be a result of chronic immune activation, a known feature of MS. Furthermore, while healthy controls showed a significant increase in mitochondrial mass upon activation, MS patients did not exhibit this change, indicating potential mitochondrial dysfunction or altered energy metabolism in MS.

BCL6–HHEX Interaction: A Perturbed Relationship in MS
Another intriguing finding is the epistatic interaction between HHEX and BCL6, another MS-risk gene. BCL6 is known to directly repress HHEX expression, and this study found that this reciprocal repression is disrupted in MS patients. In healthy controls, the BCL6 rs2590438 SNP influenced HHEX expression, but this effect was absent in MS patients. This disruption could contribute to the dysregulation of immune responses in MS, highlighting the complex genetic interactions that underlie the disease.

Conclusion
The study underscores the importance of understanding genetic variants like rs7923837 in the context of MS. The SNP not only affects HHEX expression and localization but also has broader implications for immune cell metabolism and gene regulation. These findings contribute to a growing body of evidence that MS is a disease driven by intricate genetic and metabolic factors. By unraveling these connections, we move closer to developing targeted therapies that address the root causes of MS rather than just its symptoms.

Understanding the genetic basis of MS through studies like this one opens up new avenues for research and potential therapeutic strategies, emphasizing the need for further exploration of HHEX and its associated pathways in MS pathogenesis.

References:
González-Jiménez, A., López-Cotarelo, P., Agudo-Jiménez, T., Martínez-Ginés, M., García-Domínguez, J. M., Urcelay, E., & Espino-Paisán, L. (2022). Unraveling the influence of HHEX risk polymorphism rs7923837 on multiple sclerosis pathogenesis. International Journal of Molecular Sciences, 23(14), 7956.