Variants of TNF Genes and Their Role in Familial Multiple Sclerosis

Multiple sclerosis (MS) is a chronic autoimmune disorder that affects the central nervous system (CNS), and genetic predispositions play a pivotal role in determining individual susceptibility. In this blog post, we delve into the findings of a study by Torre-Fuentes et al., published in CNS Neuroscience & Therapeutics in 2020, which explores how variants in genes encoding tumor necrosis factor (TNF) receptors and ligands contribute to familial MS. This study provides new insights into the genetic underpinnings of MS, with a particular focus on the TNF pathway—a key regulator of inflammation and immune responses.

Introduction: The TNF Pathway and MS
TNF-α is a cytokine critical to immune regulation and inflammation, processes intimately involved in MS pathogenesis. The TNF superfamily consists of several receptors and ligands that mediate cellular responses like apoptosis, cell proliferation, and differentiation. This study focuses on identifying specific genetic variants within this pathway that could be linked to an increased risk of familial MS. By utilizing whole-exome sequencing, the authors analyzed 116 individuals from 19 families with at least two MS patients.

Methods: Genetic Exploration of Familial MS
The study used whole-exome sequencing to identify variants in genes encoding TNF receptors, ligands, and proteins regulating TNF expression. The analysis was conducted on DNA from blood samples, comparing MS patients, individuals with other autoimmune diseases (AIDs), and healthy individuals within these families. The sequencing data were evaluated for variants that may alter protein function, potentially affecting TNF-mediated immune regulation.

Key Findings: TNF Variants and MS Susceptibility
Although none of the identified variants reached statistical significance after correction for multiple comparisons, several variants showed trends towards significance, indicating their potential involvement in MS susceptibility.

TNFRSF19 Variant (rs35041805): This rare variant, previously unlinked to MS, was more frequent in patients with MS. It segregated with the disease in two families, suggesting a novel association with MS. TNFRSF19 encodes TROY, a receptor involved in CNS functions, including the inhibition of myelin inhibitors—processes that are highly relevant to MS pathology.

LT-β Variant (rs4647187): Found at higher frequencies in MS patients, this variant is located within the major histocompatibility complex (MHC) region and has been associated with other autoimmune conditions like rheumatoid arthritis. Its role in familial MS could represent a broader autoimmune susceptibility.

LT-α Variants (rs1041981 and rs2229094): These variants were observed in two families with MS and are particularly intriguing due to their higher-than-expected frequencies compared to population data. LT-α, a cytokine involved in the immune response, has been previously linked to MS, and its altered function could influence the disease's progression.

TNFSF10 (TRAIL) Receptor Variant (rs1047266): This variant in the TNFRSF10B gene, which encodes a receptor for the TNFSF10 (TRAIL) protein, showed a higher frequency in MS patients. TRAIL is thought to have a role in immune tolerance and CNS inflammation, suggesting a possible connection to MS.

TNFAIP2 Variant (rs1132339): This variant showed a strong association with autoimmune diseases in the cohort, particularly when present in homozygosity. Although its connection to MS is novel, it warrants further exploration due to its involvement in inflammatory pathways.

Pedigree Analysis: Family-Specific Associations
By analyzing pedigrees, the researchers were able to establish associations between specific TNF gene variants and MS within families. For instance, variants in TNFRSF10A and TNFRSF19 segregated with MS in multiple generations. The same was true for variants in genes regulating TNF expression, such as LITAF and TNFAIP2, highlighting the complexity of familial MS and the potential for multiple genetic factors to influence disease risk.

Implications for MS Research
This study underscores the importance of considering genetic variants within immune signaling pathways, such as the TNF pathway, when assessing MS risk. The identification of rare variants in genes like TNFRSF19 and LT-α suggests that alterations in TNF signaling may contribute to disease development, particularly in familial cases. While the sample size was relatively small and some findings did not reach statistical significance, these preliminary results offer a foundation for future studies to validate the role of these variants in larger cohorts.

Conclusion: TNF Pathway and Familial MS The study by Torre-Fuentes et al. represents an important step forward in understanding the genetic factors underlying familial MS. By focusing on the TNF signaling pathway, the researchers identified several gene variants that may influence MS susceptibility. Further research is needed to confirm these associations and explore how these genetic alterations affect immune responses in MS patients. Nonetheless, the findings highlight the complex interplay between genetics and immune regulation in autoimmune diseases like MS.

Reference:
Torre‐Fuentes, L., Matías‐Guiu, J. A., Pytel, V., Montero‐Escribano, P., Maietta, P., Álvarez, S., ... & Matías‐Guiu, J. (2020). Variants of genes encoding TNF receptors and ligands and proteins regulating TNF activation in familial multiple sclerosis. CNS Neuroscience & Therapeutics, 26(11), 1178-1184.