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Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus.
Neurology 2013; 81(22):1891-9Neur

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.

Authors+Show Affiliations

From the Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry (L.O., I.Y.F., M.L., B.T.K., Z.X., P.L.D.), Department of Neurology, Partners MS Center, Center for Neurologic Diseases (B.C.H., T.C., S.J.K., H.L.W., P.L.D.), and Center for Neurological Imaging, Department of Radiology (C.R.G.), Brigham and Women's Hospital and Harvard Medical School, Boston, MA; Program in Medical & Population Genetics (L.O., I.Y.F., M.L., B.T.K., Z.X., P.L.D.), Broad Institute of Harvard University and the Massachusetts Institute of Technology, Cambridge; and the Department of Neurology and Immunobiology (D.A.H.), Yale School of Medicine, New Haven, CT.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

24174586

Citation

Ottoboni, Linda, et al. "Clinical Relevance and Functional Consequences of the TNFRSF1A Multiple Sclerosis Locus." Neurology, vol. 81, no. 22, 2013, pp. 1891-9.
Ottoboni L, Frohlich IY, Lee M, et al. Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus. Neurology. 2013;81(22):1891-9.
Ottoboni, L., Frohlich, I. Y., Lee, M., Healy, B. C., Keenan, B. T., Xia, Z., ... De Jager, P. L. (2013). Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus. Neurology, 81(22), pp. 1891-9. doi:10.1212/01.wnl.0000436612.66328.8a.
Ottoboni L, et al. Clinical Relevance and Functional Consequences of the TNFRSF1A Multiple Sclerosis Locus. Neurology. 2013 Nov 26;81(22):1891-9. PubMed PMID: 24174586.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Clinical relevance and functional consequences of the TNFRSF1A multiple sclerosis locus. AU - Ottoboni,Linda, AU - Frohlich,Irene Y, AU - Lee,Michelle, AU - Healy,Brian C, AU - Keenan,Brendan T, AU - Xia,Zongqi, AU - Chitnis,Tanuja, AU - Guttmann,Charles R, AU - Khoury,Samia J, AU - Weiner,Howard L, AU - Hafler,David A, AU - De Jager,Philip L, Y1 - 2013/10/30/ PY - 2013/11/1/entrez PY - 2013/11/1/pubmed PY - 2014/1/22/medline SP - 1891 EP - 9 JF - Neurology JO - Neurology VL - 81 IS - 22 N2 - 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. SN - 1526-632X UR - https://www.unboundmedicine.com/medline/citation/24174586/Clinical_relevance_and_functional_consequences_of_the_TNFRSF1A_multiple_sclerosis_locus_ L2 - http://www.neurology.org/cgi/pmidlookup?view=long&pmid=24174586 DB - PRIME DP - Unbound Medicine ER -