Unraveling the Genetic Complexity of Multiple Sclerosis: The Role of Non-HLA Genes
Multiple sclerosis (MS) is a chronic, autoimmune disorder characterized by inflammation and neurodegeneration within the central nervous system (CNS). Affecting approximately 2.2 million people globally, MS is marked by the progressive loss of the myelin sheath, leading to sensory, motor, and cognitive disturbances. While the etiology of MS remains elusive, it is believed to arise from a complex interplay of genetic and environmental factors.
The human leukocyte antigen (HLA) genes, particularly those located on chromosome 6, have long been recognized as the major genetic contributors to MS susceptibility. However, recent studies highlight the significant role of non-HLA genes in the disease's pathogenesis. This review article by Jamilah Borjac et al. delves into the non-HLA genetic variants implicated in MS, providing a comprehensive overview of their contribution to disease onset and progression.
Key Non-HLA Genes Associated with MS
Cluster of Differentiation 58 (CD58)
Function: Encodes a glycosylated cell adhesion molecule involved in T-cell activation.
Genetic Variants: The rs2300747 and rs12044852 polymorphisms have been studied extensively. The G allele of rs2300747 is protective, while the CC genotype of rs12044852 correlates with MS severity and a negative response to interferon-beta therapy.
Cluster of Differentiation 6 (CD6)
Function: Plays a role in T-cell activation and differentiation, crucial for leukocyte migration across the blood-brain barrier.
Genetic Variants: The rs17824933 polymorphism is associated with decreased CD6 expression, impacting T-cell proliferation. Anti-CD6 monoclonal antibodies are being explored as potential MS therapies.
C-type Lectin Domain Containing 16A (CLEC16A)
Function: Involved in immune regulation, particularly antigen presentation.
Genetic Variants: The rs12927355 polymorphism is associated with increased CLEC16A expression in MS patients. Vitamin D treatment can modulate its expression, suggesting a role in MS pathogenesis.
Cytochrome P450 Family 27 Subfamily B Member 1 (CYP27B1)
Function: Converts vitamin D to its active form, impacting immune response regulation.
Genetic Variants: The rs703842 and rs118204009 polymorphisms show inconsistent associations with MS across different populations. Vitamin D levels are generally lower in MS patients regardless of genotype.
Forkhead Box P3 (FoxP3)
Function: Regulates T-cell activity by promoting regulatory T (Treg) cell function.
Genetic Variants: The rs3761548 polymorphism is linked to reduced FoxP3 expression and impaired Treg function in MS. Treatments like interferon-beta can restore FoxP3 levels, highlighting its potential as a therapeutic target.
Interleukin 2 Receptor Alpha (IL2-Rα)
Function: Part of the IL2 receptor system, essential for T-cell proliferation and survival.
Genetic Variants: Polymorphisms like rs2104286 are associated with MS susceptibility. Hypomethylation of IL2-Rα and increased expression are observed in MS patients.
Interleukin 7 Receptor Alpha (IL7-Rα)
Function: Plays a critical role in the maturation of B and T cells.
Genetic Variants: The rs6897932 polymorphism affects alternative splicing of IL7-Rα, influencing MS risk. Various SNPs in IL7-Rα are linked to altered gene expression and MS susceptibility.
Conclusion
The intricate genetic landscape of MS extends beyond the HLA region, with numerous non-HLA genes contributing to the disease's complexity. Understanding these genetic variants can pave the way for personalized treatment strategies and improved disease management. Future research should focus on validating these associations across diverse populations and exploring their functional implications in MS pathogenesis.
References
Borjac, J., Matar, A., Merheb, M., Vazhappilly, C.G., & Matar, R. (2023). Non-HLA Genes and Multiple Sclerosis. The Open Biotechnology Journal, 17, e187407072303030. DOI: 10.2174/18740707-v17-e230316-2022-25.
