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Variants of genes encoding TNF receptors and ligands and proteins regulating TNF activation in familial multiple sclerosis.

ABSTRACT: INTRODUCTION:Numerous genetic variants have been associated with susceptibility to multiple sclerosis (MS). Variants located in genes involved in specific pathways, such as those affecting TNF-?, can contribute to the risk of MS. The purpose of this study was to determine whether variants of these genes are associated with greater risk of MS. METHODS:We used whole-exome sequencing to study genes coding for TNF-? receptors and ligands, and proteins promoting TNF-? expression in 116 individuals from 19 families including at least two MS patients. We compared patients with MS, patients with other autoimmune diseases, and healthy individuals. RESULTS:Greater polymorphism was observed in several genes in families with familial MS compared to the general population; this may reflect greater susceptibility to autoimmune diseases. Pedigree analysis also revealed that LT-? variants rs1041981 and rs2229094 and LT-? variant rs4647197 were associated with MS and that LT-? variant rs4647183 was associated with other autoimmune diseases. The association between autoimmune disease and TNFAIP2 variant rs1132339 is particularly noteworthy, as is the fact that TNFAIP6 variant rs1046668 appears to follow a recessive inheritance pattern. CONCLUSIONS:Our findings support the idea that the risk of familial MS is associated with variants of signaling pathways, including those involving TNF-?.

SUBMITTER: Torre-Fuentes L

PROVIDER: S-EPMC7564193 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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Variants of genes encoding TNF receptors and ligands and proteins regulating TNF activation in familial multiple sclerosis.

Torre-Fuentes Laura L Matías-Guiu Jordi A JA Pytel Vanesa V Montero-Escribano Paloma P Maietta Paolo P Álvarez Sara S Gómez-Pinedo Ulises U Matías-Guiu Jorge J

CNS neuroscience & therapeutics 20200920 11

<h4>Introduction</h4>Numerous genetic variants have been associated with susceptibility to multiple sclerosis (MS). Variants located in genes involved in specific pathways, such as those affecting TNF-α, can contribute to the risk of MS. The purpose of this study was to determine whether variants of these genes are associated with greater risk of MS.<h4>Methods</h4>We used whole-exome sequencing to study genes coding for TNF-α receptors and ligands, and proteins promoting TNF-α expression in 116 ...[more]

PMID: 32951330

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Project description:An imbalance of TNF signalling in the inflammatory milieu generated by meningeal immune cell infiltrates in the subarachnoid space in multiple sclerosis (MS), and its animal model may lead to increased cortical pathology. In order to explore whether this feature may be present from the early stages of MS and may be associated with the clinical outcome, the protein levels of TNF, sTNF-R1 and sTNF-R2 were assayed in CSF collected from 122 treatment-naïve MS patients and 36 subjects with other neurological conditions at diagnosis. Potential correlations with other CSF cytokines/chemokines and with clinical and imaging parameters at diagnosis (T0) and after 2 years of follow-up (T24) were evaluated. Significantly increased levels of TNF (fold change: 7.739; p < 0.001), sTNF-R1 (fold change: 1.693; p < 0.001) and sTNF-R2 (fold change: 2.189; p < 0.001) were detected in CSF of MS patients compared to the control group at T0. Increased TNF levels in CSF were significantly (p < 0.01) associated with increased EDSS change (r = 0.43), relapses (r = 0.48) and the appearance of white matter lesions (r = 0.49). CSF levels of TNFR1 were associated with cortical lesion volume (r = 0.41) at T0, as well as with new cortical lesions (r = 0.56), whilst no correlation could be found between TNFR2 levels in CSF and clinical or MRI features. Combined correlation and pathway analysis (ingenuity) of the CSF protein pattern associated with TNF expression (encompassing elevated levels of BAFF, IFN-γ, IL-1β, IL-10, IL-8, IL-16, CCL21, haptoglobin and fibrinogen) showed a particular relationship to the interaction between innate and adaptive immune response. The CSF sTNF-R1-associated pattern (encompassing high levels of CXCL13, TWEAK, LIGHT, IL-35, osteopontin, pentraxin-3, sCD163 and chitinase-3-L1) was mainly related to altered T cell and B cell signalling. Finally, the CSF TNFR2-associated pattern (encompassing high CSF levels of IFN-β, IFN-λ2, sIL-6Rα) was linked to Th cell differentiation and regulatory cytokine signalling. In conclusion, dysregulation of TNF and TNF-R1/2 pathways associates with specific clinical/MRI profiles and can be identified at a very early stage in MS patients, at the time of diagnosis, contributing to the prediction of the disease outcome.

Dataset Information

Variants of genes encoding TNF receptors and ligands and proteins regulating TNF activation in familial multiple sclerosis.

Publications

Variants of genes encoding TNF receptors and ligands and proteins regulating TNF activation in familial multiple sclerosis.

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