Linda Ottoboni1, Irene Y Frohlich, Michelle Lee, Brian C Healy, Brendan T Keenan, Zongqi Xia, Tanuja Chitnis, Charles R Guttmann, Samia J Khoury, Howard L Weiner, David A Hafler, Philip L De Jager. 1. 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.
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.
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.
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