|Publication Type||Journal Article|
|Year of Publication||2013|
|Authors||Ottoboni, L, Frohlich, IY, Lee, M, Healy, BC, Keenan, BT, Xia, Z, Chitnis, T, Guttmann, CR, Khoury, SJ, Weiner, HL, Hafler, DA, De Jager, PL|
|Date Published||2013 Nov 26|
|Keywords||Animals, Arginine, Chemokine CXCL10, Female, Gene Expression Regulation, Genetic Predisposition to Disease, Genotype, Glutamine, HEK293 Cells, Humans, Immunologic Factors, Longitudinal Studies, Male, Monocytes, Multiple Sclerosis, Mutation, Phorbol Esters, Receptors, Tumor Necrosis Factor, Type I, RNA Isoforms, Signal Transduction, Tumor Necrosis Factor-alpha|
OBJECTIVE: We set out to characterize the clinical impact and functional consequences of rs1800693(G), the multiple sclerosis (MS) susceptibility allele found in the TNFRSF1A locus.
METHODS: We analyzed prospectively collected data on patients with MS to assess the role of the TNFRSF1A locus on disease course and treatment response. Using archival serum samples and freshly isolated monocytes from patients with MS and healthy subjects, we evaluated the effects of rs1800693(G) and a second risk allele, R92Q, on immune function.
RESULTS: In 772 patients with MS, we see no evidence that rs1800693(G) strongly influences clinical or radiographic indices of disease course and treatment response; thus, rs1800693(G) appears to be primarily involved in the onset of MS. At the molecular level, this validated susceptibility allele generates an RNA isoform, TNFRSF1A Δ6, that lacks the transmembrane and cytoplasmic domains. While there was no measurable effect on serum levels of soluble TNFRSF1A, rs1800693(G) appears to alter the state of monocytes, which demonstrate a more robust transcriptional response of CXCL10 and other genes in response to tumor necrosis factor (TNF)-α. We also report that activation of the TNF-α pathway results in altered expression of 6 other MS susceptibility genes, including T-cell activation rho GTPase activating protein (TAGAP) and regulator of G-protein signaling 1 (RGS1), which are not previously known to be responsive to TNF-α.
CONCLUSIONS: The MS rs1800693(G) susceptibility allele affects the magnitude of monocyte responses to TNF-α stimulation, and the TNF pathway may be one network in which the effect of multiple MS genes becomes integrated.
|PubMed Central ID||PMC3843384|
|Grant List||K08 NS079493 / NS / NINDS NIH HHS / United States |
R01 NS067305 / NS / NINDS NIH HHS / United States