Table 1.
Genetic variants and their possible mechanism of association with MS progression.
| Sr. No. | Gene | Genetic Variants (SNPs) | Putative Mechanism Involved | Types of MS | References |
|---|---|---|---|---|---|
| 1. | HLA-DRB1 | HLA-DRB115:01 | ↑ Influencing specific antigens presentation to immune cells and inappropriate immune response against self-antigens ↑Inflamation and injury to CNS |
RRMS | [48] |
| 2. | DYSF–ZNF638 | rs10191329 | ↓Median time to needing a walking aid; a median of 3.7 years (in homozygous carriers) ↑Brainstem abnormalities and cortical pathology in the brain tissue |
Relapsing form of MS | [30] |
| 3. | IL-2RA | rs2104286 (intronic) | Changes in the ratio of soluble to membrane-bound molecules ↑sIL2RA and CD25 expression on CD4+ T cells in MS |
RRMS | [70, 195] |
| 4. | IL7R | T2441 rs6897932 (exon-6) |
↑ Exon 6 skipping ↑mRNA fraction and changes in the soluble/membrane-bound ratio ↑Serum IL7R |
RRMS | [75, 84] |
| 5. | TNFRSF1A | P46L (rs1800693) (intron-6) R92 Q (rs4149584) (exon-4) |
↑Lacking exon-6, altering the soluble/membrane-bound ratio; ↑> TNFR1 ↓Frequency variants in the sporadic case, altering the contact region between TNF-α and its receptor ↑Electrostatic interactions and ligand interaction alter the receptor's signalling pathway |
RRMS Relapsing MS |
[86, 89, 196] |
| 6. | CD40 | rs1883832 T | CD40-CD40L interaction immune checkpoint ↑Both innate and adaptive immune response and inflammatory response |
RRMS | [118, 197] |
| 7. | CD58 | rs2300747 (intronic) | ↑Expression of CD58 in mononuclear cells of CIS and RRMS patients | RRMS and CIS | [93] |
| 8. | CLEC16A | rs12708716 | ↑ Levels of two distinct CLEC16A transcripts in the thymus (not in blood); splicing regulation may be cell- or thymus-specific | Relapsing MS | [138] |
| 9. | IRF8 | rs17445836G (intronic) | The variant is linked to: ↓Serum type-I IFN levels ↑ IRF8 expression |
SPMS | [145] |
| 10. | CXCR5 | rs10892307 (intronic) | Immunophenotyping using PBMCs; f expressing CXCR5 | Relapsing MS | [155] |
| 11. | CCR5 | CCR5- Δ32 | Receptor (shortened and non-functional) ↑T cell migration to inflammatory areas |
PPMS, RRMS, and SPMS | [164] |
| 12. | CTLA4 | −319C/T (rs5742909); +49A/G (rs231775); CT60A/G (rs3087243); Jo31G/T (rs11571302) | Altered immunological response or autoimmune disease susceptibility | RRMS, SPMS | [172] |
| 13. | CD226 | rs763361; rs727088 | ↓Expression on memory T cells in MS patients | Relapsing MS | [182] |
| 14. | DNM3-PIGC | rs149097173 | ↑Genetic enrichment in CNS tissues | RRMS | [30] |
| 15. | TYK2 | rs34536443 | ↓Tfh cells, memory B cells, and IFNAR signalling | RRMS | [185] |
| 16. | SLAMF1 | rs3753381 | ↑Activity of SLAMF1 promotor b> twofold ↑Activity of enhancer-E |
Relapsing MS | [192] |
| 17. | TNFAIP3 | rs10499194 (intronic) |
Located in the intergenic region upstream of TNFAIP3 In vitro ChIP-seq data set generated by the ENCODE project indicates that it lies within a target site for several transcription factors, including JunD, BAF155, and DNase hypersensitive site |
RRMS, SPMS | [178] |
| 18. | EV15 | rs10735781 rs6680578 |
Alters affinity for binding of PAX6 transcription factors | RRMS | [44] |
Note: The table displays data regarding various genetic variations and their respective processes that have been linked to distinct forms of MS, including Relapsing-remitting MS (RRMS), Secondary Progressive MS (SPMS), and Clinically Isolated Syndrome (CIS). The genetic variations are associated with the advancement of the disease and function by exerting influence on the numerous cellular and molecular mechanisms underlying MS pathology. These genetic variations alter the immune response, and their heightened expression disrupts the progression of neurodegenerative processes.
Abbreviations: SNP: Single nucleotide polymorphism, MS: Multiple sclerosis, HLA: Human leukocyte antigen, PPMS: Primary progressive MS, IL-2RA: Interleukin-2 receptor alpha, TNFRSF1A: Tumor necrosis factor receptor superfamily 1A, CD40: Cluster of differentiation 40, CD58: Lymphocyte function antigen-3 (LFA-3), CLEC16A: C-type lectin domain containing 16A, IRF8: Interferon regulatory factor 8, CXCR5: C-X-C Chemokine receptor type 5, CCR5: C-C chemokine receptor 5, CTLA4: Cytotoxic T-lymphocyte associated protein 4, SPMS: Secondary progressive MS, RRMS: Relapsing-remitting MS, PAX: Paired box protein 6.