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Abstract
Objective: We set out to characterize the clinical impact and functional consequences of rs1800693G, 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 rs1800693G and a second risk allele, R92Q, on immune function.
Results: In 772 patients with MS, we see no evidence that rs1800693G strongly influences clinical or radiographic indices of disease course and treatment response; thus, rs1800693G 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, rs1800693G 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 rs1800693G 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.
GLOSSARY
- AA=
- amino acids;
- BWH=
- Brigham and Women’s Hospital;
- CI=
- confidence interval;
- GA=
- glatiramer acetate;
- IFN-β=
- interferon-β;
- MAPK=
- mitogen-activated protein kinase;
- MS=
- multiple sclerosis;
- MSSS=
- Multiple Sclerosis Severity Scale;
- NF=
- nuclear factor;
- PBMC=
- peripheral blood mononuclear cell;
- sTNFRSF1A=
- soluble TNFRSF1A;
- TNF=
- tumor necrosis factor;
- TRAPS=
- TNF receptor–associated periodic syndrome
Footnotes
↵* These authors contributed equally to this work.
Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.
Editorial, page 1886
Supplemental data at www.neurology.org
- Received February 17, 2013.
- Accepted in final form July 31, 2013.
- © 2013 American Academy of Neurology
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