The Polygenic Nature of Multiple Sclerosis: Genetic Variants, Immunological Modulation, and Environmental Connections

Multiple Sclerosis (MS), a debilitating inflammatory disorder of the central nervous system characterized by demyelination, is significantly influenced by polygenic variations. Although the precise cause of MS remains unclear, it is believed to arise from a complex interplay of genetic and environmental factors. Recent investigations have focused on the polygenic nature of genetic alterations linked to MS risk. This review highlights the critical role of these genetic variants in shaping disease susceptibility and progression. Specific Human Leukocyte Antigen (HLA) alleles, such as HLA-DRB1*15:01, HLA-DRB50*101, HLA-DR2+, HLA-DQ6, DQA 0102, and DQB1 0602, are implicated in immune modulation, significantly increasing the risk of developing MS. Additionally, Genome-wide Association Studies (GWAS) have identified non-HLA genetic variants that contribute to MS susceptibility, including IL-2RA (rs2104286), IL-7R (rs6897932), CD40 (rs1883832 T), CD58 (rs2300747), and others, each playing a role in immune regulation and disease progression. Dysfunctions in genes regulating myelin integrity, such as MOG (Myelin Oligodendrocyte Glycoprotein), MAG (Myelin-associated Glycoprotein), and PLP1 (Proteolipid Protein 1), further drive MS pathogenesis. Moreover, viral infections, notably Epstein-Barr Virus (EBV), Human Herpesvirus 6 (HHV-6), and measles virus, may exacerbate the development of MS by triggering immune responses. Understanding the contribution of these genetic and viral factors may shed light on the complex etiology of MS. Polygenic Risk Scores (PRS) provide a valuable tool for estimating MS susceptibility based on the cumulative effect of genetic variants. However, translating these genetic insights into clinical practice requires further validation, including environmental considerations. Investigating MS polygenicity could lead to personalized therapies, enhancing diagnosis, prognosis, and treatment, ultimately improving outcomes for MS patients.