Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus.

Neurology
Authors
Keywords
Abstract

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.

Year of Publication
2013
Journal
Neurology
Volume
81
Issue
22
Pages
1891-9
Date Published
2013 Nov 26
ISSN
1526-632X
URL
DOI
10.1212/01.wnl.0000436612.66328.8a
PubMed ID
24174586
PubMed Central ID
PMC3843384
Links
Grant list
K08 NS079493 / NS / NINDS NIH HHS / United States
R01 NS067305 / NS / NINDS NIH HHS / United States