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

Abstract

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.

Keywords: Multiple sclerosis; demyelination; diagnosis.; genetic variants; genome-wide association study; polygenic risk score.

Fig. (1)

The interplay of genetic, immune, and environmental factors in MS pathogenesis. This diagram depicts the complex interaction among genetic, immune response, and environmental factors in the progression of MS. The diagram demonstrates that the aetiology of MS is complex. The figure illustrates how genetic predisposition, particularly in the MHC region, can impact MS risk. The genetic variants of HLA genes are divided into classes I, II, and III. A potent allele, HLA-DRB1*1501, is strongly associated with MS progression in class-II HLA genetic variants. The diverse environmental factors include EBV, vitamin D deficiency, smoking, gastric microbiome, stress, and location. These variables alter the function and activation of the immune system, initiating or aggravating MS symptoms. T cells, B cells, macrophages, and cytokines interact in a circular circuit during the immune response. The diagram illustrates how genetic predisposition and environmental factors can result in an abnormal immune response that infiltrates auto-reactive immune cells into the CNS. These cells demyelinate the myelin sheath, which protects nerve fibres, resulting in central inflammation and additional neurological impairments. In the development of MS, the figure highlights the complex interactions among genetic predisposition, environmental stimuli, and immune response dysregulation. It demonstrates that these three factors may contribute to oligodendrocyte degradation, MBP damage, and myelin damage, all of which increase the likelihood of developing the disease. Abbreviations: MS: Multiple sclerosis, MHC: Major histocompatibility complex, HLA: Human leukocyte antigen, EBV: Epstein Barr virus, HLA-DRB1*1501: Human leukocyte antigen class II, DR beta 1 precursor, MBP: Myelin basic protein.

Fig. (2)

Role of genetic variants in the progression of MS. The graphic diagram illustrates the significant role of specific genetic variations in advancing MS. The haplotypes rs2104286, rs11256593, rs6897932, rs4149584, rs1800693, rs1883832 T, and rs2300747 are associated with important immune-related genes. The discovered SNPs have been found to play a role in controlling the immune response, leading to alterations in the severity and progression of MS. The immunological regulation and cell communication processes require the participation of several molecules, including IL-2RA, IL-7RA, TNFRSF1A, CD40, and CD58. The capacity of genetic sequences to influence the functioning of immune cells, including T cells and antigen-presenting cells, can exert an effect on the pathogenesis and advancement of MS. Specific alleles within these genes, namely rs2104286 and rs11256593, induce T cell activation and CD25 expression in CD4+ cells, along with a modified immunological response, resulting in heightened inflammation and subsequent demyelination. The IL-7RA allele rs6897932 is associated with exon-6 skipping, leading to increased levels of IL-7R in the bloodstream and mRNA. This molecular alteration has been implicated in the development of neuroinflammation and demyelination. The interaction between Tumour Necrosis Factor (TNF) and its receptor TNFR1 leads to the activation of inflammatory responses, cell death, and disruption of the Blood-brain Barrier (BBB). These processes have a role in the evolution of MS. The genetic variations rs4149584 and rs1800693 in the TNFRSF1A gene are responsible for encoding the TNFR1 protein. The genetic variant rs1883832 represents a polymorphism located within the CD40 gene. T activation elicits a response in immune cells, leading to an increase in the production of pro-inflammatory cytokines. The genetic variant rs2300747 has been identified as a CD58 variant that has been found to enhance the presence of several immune cells, such as APC cells (including macrophages and dendritic cells), T cells, and NK cells. This variant is associated with an overexpression of pro-inflammatory cytokines, disrupting the immune system. Consequently, this disruption contributes to inflammation, demyelination, and neuronal damage characteristic of MS. Abbreviations: IL-2RA: Interleukin-2 receptor alpha, CD40: Cluster of differentiation 40, TNF: Tumor necrosis factor, TNFR1: Tumor necrosis factor receptor 1, APC: Antigen-presenting cells, BBB: Blood-brain barrier, NK: Natural killer cells.

Fig. (3)

Genetic variants associated with T-cell activation, B-cell function, and immune cell migration in MS progression. The diagram depicts the notable contributions of distinct genetic variations to the development of MS. The genetic variations included in this set comprise the haplotypes rs12708716, rs17445836G, rs10191329, rs10892307, CCR5-32, rs5742909, rs231775, rs3087243, and rs11571302. Every variant is correlated with specific elements of MS progression. The genetic variant CLE16A (rs12708716) has been associated with the control of the immune system. It can potentially affect the inflammatory response, which plays a role in the development and progression of MS. The genetic variant IRF8 (rs17445836G) regulates immune responses and can potentially influence the equilibrium between pro-inflammatory and anti-inflammatory signals in MS. The genetic variant DYSF-ZNF638 (rs10191329) can affect the mechanisms involved in brain repair, potentially altering the remyelination process and the integrity of neurons. These factors are known to have significant implications for the progression of MS. The genetic variant CXCR5 (rs10892307) has been found to correlate with the movement and positioning of B-cells inside the CNS. This relationship has the potential to impact the development of inflammatory lesions that are commonly associated with MS. The CCR5 (CCR5-Δ32) gene variant is linked to the migration of immune cells. It potentially impacts the infiltration of immune cells into the CNS, hence playing a role in the development of chronic inflammation observed in MS. The variations rs5742909, rs231775, rs3087243, and rs11571302 of the CTLA4 gene are associated with immunological modulation and T-cell responses. The modulation of CTLA-4 signalling can potentially affect the equilibrium between immunological activation and repression, exerting an influence on the overall progression of MS. Abbreviations: IRF8: Interferon-regulatory factor 8, DYSF-ZNF638: Dysferlin zinc finger protein 638, CXCR5: C-X-C chemokine receptor 5, CCR5: C-C chemokine receptor 5, CTLA4: Cytotoxic T-lymphocyte–associated antigen 4.

Fig. (4)

Role of numerous genetics variants and their pathways in the progression of MS. The diagram depicts the correlation among the TYK2 gene Single Nucleotide Polymorphism (SNP) rs34536443, the CD226 SNP rs763361, and the DNM3-PIGC SNP rs149097173 in the context of neurodegenerative diseases, such as MS. TYK2, belonging to the Janus Kinase (JAK) family, has been identified as a potential hereditary candidate gene associated with autoimmune disorders due to its role in regulating signalling pathways for various cytokines, particularly type I interferon. The non-receptor protein TYK2 interacts with the inactive IFN-I Receptor (IFNAR1) located on the cellular membrane. The process of IFN-binding to IFNAR1 leads to the phosphorylation of STAT 1 and 2, activating the TYK2 and JAK1 proteins. Many genes triggered by Interferons (IFNs) are subject to tight regulation by heterodimers of STAT1 and STAT2 within the nucleus. Autoimmune diseases often arise due to aberrant production of Interferon type I (IFN-I), other cytokines, or members of the JAK kinase family by immune cells. TYK2 influences various cellular processes, including but not limited to its involvement in the IFN-I and other type I and II cytokine receptor pathways. Additionally, TYK2 has a role in modulating natural killer cell activity and regulating the production of B and Treg cells. Furthermore, TYK2 is involved in the differentiation of Th1 and Th17 cells. There exists a correlation between dysregulated expression of TYK2 and autoimmune diseases. The CD226 genetic variant rs763361 holds significance in the activation of regulatory T cells, which are pivotal in the aberrant regulation that contributes significantly to the etiopathogenesis of MS. T lymphocytes undergo activation inside the lymphatic system and subsequently infiltrate the CNS utilizing arterial circulation in the context of MS. Upon arrival, T cells secrete pro-inflammatory cytokines, thereby inducing inflammation and resulting in tissue damage. The process described results in the degradation of myelin, nerve fibres, and the oligodendrocytes responsible for myelin production. A potential relationship was identified between rs149097173 in the DNM3-PIGC gene and significant genetic enrichment in CNS tissues. Elevated expression of the rs149097173 allele was found to be associated with cortical and brain-stem damage, subsequently leading to demyelination and an increased risk of MS. Abbreviations: TYK2: Tyrosine kinase 2, JAK: Janus kinase, DNM3-PIGC: Dynamin 3 phosphatidylinositol glycan anchor biosynthesis class C, IFN-1: Interferon-1, Th17: T-helper cells 17.