Title : The role of TNF superfamily genes polymorphisms in multiple sclerosis
Abstract:
Introduction: Data on the genetic heterogeneity of autoimmune diseases of the nervous system, among which the most common is multiple sclerosis (MS), stimulate many studies to search for links between individual gene polymorphisms and the risk of developing diseases, their clinical course and response to treatment, the results of which contribute to the understanding of immunogenetics neurological disorders. Proinflammatory cytokines are key participants in the pathogenesis of MS, among which special attention is paid to the tumor necrosis factor (TNF) superfamily.
Materials and Methods: We studied the role of the rs1800629 polymorphism of the TNF-α gene; the rs4149584 polymorphism of the TNFRSF1A gene; and the rs6074022, rs1883832, rs1535045, and rs11086996 polymorphisms of the CD40 gene in the onset, clinical course, and response to treatment in multiple sclerosis in a group of 152 patients living in Tomsk region, whose mean age was 35.0 ± 11.2 years. The study group was dominated by women (the sex ratio was 1.9:1), the median duration of illness was 12 [9, 18] years, the mean EDSS score was 3.3 ± 1.7. A total of 707 volunteers without autoimmune diseases and pathology of the nervous system were included in the control group.
Results: Analysis of the results obtained by the distribution of genotypes of the studied genes showed a connection between the C allele (OR = 1.46; 95%CI [1.12 - 1.92]; p = 0.007) and the CT genotype (OR = 1.47; 95%CI [ 1.03 - 2.10]; p = 0.015) of the polymorphic locus rs6074022 of the CD40 gene with the risk of developing the disease, which at the same time influenced the development of optic neuritis at the onset of MS (OR = 1.96; 95% CI [1, 09 - 3.53]; p = 0.03 for the C allele and OR = 2.39; 95%CI [1.04 - 5.49]; p = 0.04 for the CT genotype). The C allele (OR = 2.11; 95%CI [1.10 - 4.08]; p = 0.04) of the rs1883832 polymorphism of the CD40 gene was associated with more rapid progression of the disease, and the CC genotype (p = 0.03) This polymorphism, along with the GG genotype (p = 0.03) of the rs1800629 polymorphism of the TNF-α gene, showed an association with a higher frequency of MS exacerbations. The influence on the development of resistance to pathogenetic therapy was shown by the A allele (OR = 4.77; 95%CI [1.07 - 21.35]; p = 0.04) and the AG genotype (OR = 5.90; 95%CI [ 1.12 - 31.02]; p = 0.04) polymorphism rs4149584 of the TNFRSF1A gene.
Conclusion: The polymorphisms of the TNF superfamily genes we studied show a significant relationship with both the risk of developing the disease and the clinical features of the disease and the response to first- and second-line DMD therapy. However, it is necessary to continue the search to obtain more information on the effect of cytokine gene polymorphisms on MS in different patient populations and to expand the knowledge base about the role of this group of genes in the development and course of immunopathological conditions.
